Lytic cell death in metabolic liver disease
Open accessAbstract
Regulated cell death is intrinsically associated with inflammatory liver disease and is pivotal in governing outcomes of metabolic liver disease. Different types of cell death may coexist as metabolic liver disease progresses to inflammation, fibrosis, and ultimately cirrhosis. In addition to apoptosis, lytic forms of hepatocellular death, such as necroptosis, pyroptosis and ferroptosis elicit strong inflammatory responses due to cell membrane permeabilisation and release of cellular components, contributing to the recruitment of immune cells and activation of hepatic stellate cells. The control of liver cell death is of fundamental importance and presents novel opportunities for potential therapeutic intervention. This review summarises the underlying mechanism of distinct lytic cell death modes and their commonalities, discusses their relevance to metabolic liver diseases of different aetiologies, and acknowledges the limitations of current knowledge in the field. We focus on the role of hepatocyte necroptosis, pyroptosis and ferroptosis in non-alcoholic fatty liver disease, alcohol-associated liver disease and other metabolic liver disorders, as well as potential therapeutic implications.
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Damaged and dying hepatocytes release damage-associated molecular patterns, which are potent activators of the innate immune system.
“Damaged and dying hepatocytes release damage-associated molecular patterns (DAMPs); potent activators of the innate immune system (209).”
From The liver as a central "hub" of the immune system: pathophysiological implications (2025) · cites this paper as [209]
Lytic cell death pathways trigger a stronger immune response than apoptosis.
“These pathways involve rapid membrane permeabilization and release of cytoplasmic contents, triggering a stronger immune response than apoptosis (12).”
From Hepatic Stellate Cell-Immune Interactions in NASH (2022) · cites this paper as [12]
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“Inflammasome activation triggers caspase activity and promotes inflammation and fibrosis in liver disease [97], while typical activators of inflammasomes such as fatty acids, DAMPs, and uric acid upregulate NLRP3 inflammasome components.”
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“Finally, MLKL forms pore in the plasma membrane [16, 17], and increases permeability via the activation of A disintegrin and metalloproteinase (ADAM) proteases [18], Ca2+ influx by targeting the cation channel transient receptor potential melastatin related 7 (TRPM7) [19], and phosphatidylserine externalization [20].”
BackgroundApoptosis and necroptosis in the liver: a matter of life and death
Schwabe, R. F., & Luedde, T. (2018) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-018-0065-y · Cited by 582 · cited 1× · see citing works
“Necroptosis is probably the best-understood form of regulated necrosis, since it shares multiple molecular components with the extrinsic apoptotic pathway and can act as a fail-safe mechanism to ensure cell death progression when apoptosis is abnormally inhibited, which may also be relevant in pathological conditions…”
BackgroundCleavage of RIPK1 by caspase-8 is crucial for limiting apoptosis and necroptosis
Newton, K., Wickliffe, K. E., Dugger, D. L., Maltzman, A., Roose‐Girma, M., Dohse, M., Kömüves, L. G., Webster, J. D., & Dixit, V. M. (2019) · Nature · doi:10.1038/s41586-019-1548-x · Cited by 547 · cited 1× · see citing works
“Third, caspase-8 limits necroptosis by proteolytically cleaving RIPK1 [138], and the genetic absence of caspase-8 in hepatocytes does not trigger widespread necroptosis [134].”
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“In a recent study, ferroptosis inhibitors, trolox and deferiprone, suppressed necrotic cell death, infiltration of inflammatory cells, and inflammatory cytokine expression in the onset of steatohepatitis in the choline-deficient, ethionine-supplemented (CDE) diet model [108], in which hepatic cell death is an early ev…”
BackgroundMechanisms of inflammasome activation: recent advances and novel insights
Vanaja, S. K., Rathinam, V. A. K., & Fitzgerald, K. A. (2015) · Trends in Cell Biology · doi:10.1016/j.tcb.2014.12.009 · Cited by 499 · cited 1× · see citing works
“The canonical inflammasomes comprise a sensor protein belonging to the nucleotide-binding domain (NBD) and leucine-rich-repeat-(LRR)-containing (NLR) or the AIM2-like receptor (ALR) or pyrin family, an adaptor protein, apoptosis-associated speck-like protein containing a CARD (ASC), and an inactive zymogen, pro-caspas…”
BackgroundKoo, G.-B., Morgan, M. J., Lee, D., Kim, W.-J., Yoon, J.-H., Koo, J. S., Kim, S. H., Kim, S., Son, M. K., Hong, S. S., et al. (2015) · Cell Research · doi:10.1038/cr.2015.56 · Cited by 489 · cited 1× · see citing works
“Epigenetic silencing of RIPK3, in contrast, has been associated with malignant transformation in hepatocellular carcinoma cells, while reestablishment of RIPK3 expression by promoter demethylation resensitized cells to chemotherapy-induced necroptosis [89], again implying that induction of RIPK3 is context-dependent.”
BackgroundHepatocyte Death: A Clear and Present Danger
Malhi, H., Guicciardi, M. E., & Gores, G. J. (2010) · Physiological Reviews · doi:10.1152/physrev.00061.2009 · Cited by 477 · cited 1× · see citing works
“Cell death has been described as a clear and present danger for hepatocytes as they are directly exposed to portal blood from the intestines, participate in the xenobiotic metabolism of drugs and alcohol, play a central role in lipid, fatty acid, and bile acid metabolism, contact with prevalent hepatotropic viruses, a…”
BackgroundSelf-citationCleavage of RIP3 inactivates its caspase-independent apoptosis pathway by removal of kinase domain
Feng, S., Yang, Y., Mei, Y., Ma, L., Zhu, D.-E., Höti, N., Castanares, M. A., & Wu, M. (2007) · Cellular Signalling · doi:10.1016/j.cellsig.2007.05.016 · Cited by 445 · see citing works
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“In addition, liver fibrosis was strongly attenuated in Gsdmd−/− mice after MCD feeding [99].”
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Deficient Endoplasmic Reticulum-Mitochondrial Phosphatidylserine Transfer Causes Liver Disease
Hernández‐Álvarez, M. I., Sebastián, D., Vives, S., Ivanova, S., Bartoccioni, P., Kakimoto, P. A., Plana, N., Veiga, S. R., Hernandez, V. A., Vasconcelos, N., et al. (2019) · Cell · doi:10.1016/j.cell.2019.04.010 · Cited by 400 · see citing works
Self-citationThe x cystine/glutamate antiporter: A potential target for therapy of cancer and other diseases
Lo, M., Wang, Y., & Gout, P. W. (2008) · Journal of Cellular Physiology · doi:10.1002/jcp.21366 · Cited by 399 · cited 1× · see citing works
“The Xc− transporter system is composed of a regulatory subunit solute carrier family 3 member 2 (SLC3A2) and a catalytic subunit solute carrier family 7 member 11 (SLC7A11), which promotes the cellular uptake of cystine, the plasma precursor of cysteine, by exchange with glutamate [51].”
BackgroundNASH is an Infl ammatory Disorder: Pathogenic, Prognostic and Therapeutic Implications
Farrell, G. C., Rooyen, D. M. V., Gan, L. T., & Chitturi, S. (2012) · Gut and Liver · doi:10.5009/gnl.2012.6.2.149 · Cited by 396 · see citing works
Activity of caspase-8 determines plasticity between cell death pathways
Newton, K., Wickliffe, K. E., Maltzman, A., Dugger, D. L., Reja, R., Zhang, Y., Roose‐Girma, M., Modrusan, Z. D., Sagolla, M. S., Webster, J. D., et al. (2019) · Nature · doi:10.1038/s41586-019-1752-8 · Cited by 378 · cited 1× · see citing works
“apoptosis, necroptosis and pyroptosis, and prevents tissue damage [67, 68].”
BackgroundYoon, S., Kovalenko, A., Bogdanov, K., & Wallach, D. (2017) · Immunity · doi:10.1016/j.immuni.2017.06.001 · Cited by 368 · see citing works
RIPK1 and RIPK3: critical regulators of inflammation and cell death
Newton, K. (2015) · Trends in Cell Biology · doi:10.1016/j.tcb.2015.01.001 · Cited by 367 · cited 1× · see citing works
“Other functions of RIPK3 in hepatocarcinogenesis have been recognized [85], and its involvement in inflammatory signalling independent of necroptosis and mediation of cell death should not be neglected [86, 87].”
BackgroundBonkovsky, H., Jawaid, Q., Tortorelli, K., LeClair, P., Cobb, J., Lambrecht, R., & Banner, B. (1999) · Journal of Hepatology · doi:10.1016/s0168-8278(99)80032-4 · Cited by 357 · cited 1× · see citing works
“Moreover, iron accumulation from metabolic dysfunction, aggravates NASH, such as in liver siderosis observed in some NASH patients [105], and primary hemochromatosis exacerbates NASH [106], while iron removal ameliorates liver damage and serum ALT [107].”
BackgroundNelson, J. E., Wilson, L., Brunt, E. M., Yeh, M. M., Kleiner, D. E., Ünalp–Arida, A., & Kowdley, K. V. (2010) · Hepatology · doi:10.1002/hep.24038 · Cited by 354 · cited 1× · see citing works
“Moreover, iron accumulation from metabolic dysfunction, aggravates NASH, such as in liver siderosis observed in some NASH patients [105], and primary hemochromatosis exacerbates NASH [106], while iron removal ameliorates liver damage and serum ALT [107].”
BackgroundRIP3: a molecular switch for necrosis and inflammationPreprint
Moriwaki, K., & Chan, F. K.-M. (2013) · Genes & Development · doi:10.1101/gad.223321.113 · Cited by 353 · cited 1× · see citing works
“Second, RIPK3 deficiency does not phenocopy MLKL deficiency, and hence studies with RIPK3 knockout or kinase dead knock-in mice, are not sufficient to invoke necroptosis as a cause of cell death, as RIPK3 has diverse functions [137].”
BackgroundThe Structure of the Necrosome RIPK1-RIPK3 Core, a Human Hetero-Amyloid Signaling Complex
Mompeán, M., Li, W., Li, J., Laage, S., Siemer, A. B., Bozkurt, G., Wu, H., & McDermott, A. E. (2018) · Cell · doi:10.1016/j.cell.2018.03.032 · Cited by 337 · see citing works
Tilg, H., Moschen, A. R., & Szabó, G. (2016) · Hepatology · doi:10.1002/hep.28456 · Cited by 319 · see citing works
A positive feedback loop between RIP3 and JNK controls non‐alcoholic steatohepatitis
Gautheron, J., Vucur, M., Reisinger, F., Cardenas, D. V., Roderburg, C., Koppe, C., Kreggenwinkel, K., Schneider, A. T., Bartneck, M., Neumann, U. P., et al. (2014) · EMBO Molecular Medicine · doi:10.15252/emmm.201403856 · Cited by 314 · cited 3× · see citing works
“JNK activation was implicated in RIPK3-dependent liver damage and fibrosis in methionine-choline deficient (MCD) diet-fed mice, since inhibition of JNK diminished RIPK3 levels in the liver [75].”
BackgroundSelf-citationAbsence of receptor interacting protein kinase 3 prevents ethanol-induced liver injury
Roychowdhury, S., McMullen, M. R., Pisano, S. G., Liu, X., & Nagy, L. E. (2013) · Hepatology · doi:10.1002/hep.26200 · Cited by 304 · cited 3× · see citing works
“Necroptosis—The involvement of necroptosis has been suggested from studies where RIPK3 expression was induced in human ALD and in mice after ethanol exposure [84, 114].”
BackgroundResultViral infection and the evolution of caspase 8-regulated apoptotic and necrotic death pathways
Mocarski, E. S., Upton, J. W., & Kaiser, W. J. (2011) · Nature reviews. Immunology · doi:10.1038/nri3131 · Cited by 300 · cited 1× · see citing works
“These unexpected roles of caspase-8 involves the activation of the inflammasome and induction of pyroptosis under circumstances in which apoptosis and necroptosis are compromised, such as when the abundance of viral inhibitors may have driven the counteradaptation of pyroptosis as a host defence [70].”
BackgroundAccumulation of natural killer T cells in progressive nonalcoholic fatty liver disease
Syn, W.-K., Oo, Y. H., Pereira, T. A., Karaca, G. F., Jung, Y., Omenetti, A., Witek, R. P., Choi, S. S., Guy, C. D., Fearing, C. M., et al. (2010) · Hepatology · doi:10.1002/hep.23599 · Cited by 283 · cited 1× · see citing works
“In this regard, activation of resident Kupffer cells and infiltrating macrophages is a remarkable feature of NASH pathogenesis [95].”
BackgroundKnockdown of ferroportin accelerates erastin-induced ferroptosis in neuroblastoma cells.
Geng, N., Shi, B.-J., Li, S.-L., Zhong, Z., Li, Y.-C., Xua, W., Zhou, H., & Cai, J.-H. (2018) · European Review for Medical and Pharmacological Sciences · doi:10.26355/eurrev_201806_15267 · Cited by 281 · cited 1× · see citing works
“In the non-canonical pathway, increased iron uptake by transferrin receptor (TFRC) and reduced iron export by ferroportin promote oxidative damage and ferroptosis [60, 61].”
BackgroundIbrahim, S. H., Hirsova, P., & Gores, G. J. (2018) · Gut · doi:10.1136/gutjnl-2017-315691 · Cited by 278 · cited 1× · see citing works
“Finally, we note that cell death per se may be a biomarker for stressed, proinflammatory hepatocytes as recently suggested in NASH [142], and therefore, precluding cell death may not have the major impact on liver injury that we anticipate.”
BackgroundSelf-citationGasdermins and their role in immunity and inflammation
Ørning, P., Lien, E., & Fitzgerald, K. A. (2019) · The Journal of Experimental Medicine · doi:10.1084/jem.20190545 · Cited by 273 · cited 1× · see citing works
“Cleave of GSDMD occurs via a canonical inflammasome caspase-1 dependent mechanism, a non-canonical inflammasome pathway involving caspases 4, 5 or 11 [139], or in an inflammasome-independent caspase-8 mediated pathway [140].”
BackgroundNLRP3 inflammasome driven liver injury and fibrosis: roles of IL-17 and TNF in mice
Wree, A., McGeough, M. D., Inzaugarat, M. E., Eguchi, A., Schuster, S., Johnson, C. D., Peña, C. A., Geisler, L. J., Papouchado, B. G., Hoffman, H. M., et al. (2018) · Hepatology · doi:10.1002/hep.29523 · Cited by 266 · cited 1× · see citing works
“Thus, in addition to immune cells, hepatocyte pyroptosis resulting from intrinsic inflammasome activation exacerbates inflammation and fibrosis in the liver, indicating that both immune cell- and liver-specific NLRP3 inflammasome activation are essential for liver injury [101, 102].”
BackgroundA randomized, placebo-controlled trial of emricasan in patients with NASH and F1-F3 fibrosis
Harrison, S. A., Goodman, Z., Jabbar, A., Vemulapalli, R., Younes, Z. H., Freilich, B., Sheikh, M. Y., Schattenberg, J. M., Kayali, Z., Zivony, A., et al. (2020) · Journal of Hepatology · doi:10.1016/j.jhep.2019.11.024 · Cited by 260 · cited 1× · see citing works
“Recently reported, caspase inhibition with Emricasan treatment did not improve clinical outcomes nor liver histology in patients with NASH fibrosis, resulting in more liver fibrosis and hepatocyte ballooning [143, 144].”
BackgroundHeo, M. J., Kim, T. H., You, J. S., Blaya, D., Sancho‐Bru, P., & Kim, S. G. (2018) · Gut · doi:10.1136/gutjnl-2017-315123 · Cited by 256 · cited 1× · see citing works
“demonstrated that alcohol elicits caspase-1-mediated pyroptosis through overexpression of thioredoxin-interacting protein (TXNIP), a member of the α-arrestin family, and this event is reversed by miR-148a [124].”
BackgroundCaspase-8 scaffolding function and MLKL regulate NLRP3 inflammasome activation downstream of TLR3
Kang, S., Fernandes‐Alnemri, T., Rogers, C., Mayes, L., Wang, Y., Dillon, C. P., Roback, L., Kaiser, W. J., Oberst, A., Sagara, J., et al. (2015) · Nature Communications · doi:10.1038/ncomms8515 · Cited by 255 · cited 1× · see citing works
“In addition to its enzymatic role in apoptosis and necroptosis, caspase-8 acts as a scaffolding protein that together with MLKL regulates NLRP3 inflammasome activation in macrophages [69].”
BackgroundRIP kinases as modulators of inflammation and immunity
He, S., & Wang, X. (2018) · Nature Immunology · doi:10.1038/s41590-018-0188-x · Cited by 246 · cited 2× · see citing works
“For example, RIP kinases have diverse functions in addition to promoting necroptosis [90].”
BackgroundPyroptosis by caspase11/4‐gasdermin‐D pathway in alcoholic hepatitis in mice and patients
Khanova, E., Wu, R., Wang, W., Yan, R., Chen, Y., French, S. W., Llorente, C., Pan, S. Q., Yang, Q., Li, Y., et al. (2018) · Hepatology · doi:10.1002/hep.29645 · Cited by 228 · cited 1× · see citing works
“Consistently, NLRP3 deficiency ameliorated alcohol-driven liver stetaosis and injury [120], while caspase-4/11 was upregulated in liver tissue from patients with alcoholic hepatitis and in mice [121].”
BackgroundAfonso, M. B., Rodrigues, P. M., Carvalho, T., Caridade, M., Borralho, P., Cortez‐Pinto, H., Castro, R. E., & Rodrigues, C. M. P. (2015) · Clinical Science · doi:10.1042/cs20140732 · Cited by 219 · cited 2× · see citing works
“Interestingly, RIPK3 deficiency protected from liver injury, inflammation and fibrosis in MCD-fed mice [74, 75], but exacerbated liver steatosis and apoptosis, as well as adipose tissue inflammation, insulin resistance and glucose intolerance induced by high-fat diet [79, 81].”
BackgroundSelf-citationMolecular crosstalk between apoptosis, necroptosis, and survival signaling
Berghe, T. V., Kaiser, W. J., Bertrand, M. J. M., & Vandenabeele, P. (2015) · Molecular & Cellular Oncology · doi:10.4161/23723556.2014.975093 · Cited by 203 · cited 1× · see citing works
“There are considerable crosstalk regulations between apoptosis and necroptosis in DR signalling pathways [21], and it seems that one cannot be achieved without inhibiting the other.”
BackgroundLoguercio, C., Girolamo, V. D., de Sio, I., Tuccillo, C., Ascione, A., Baldi, F., Budillon, G., Cimino, L., Carlo, A. D., Marino, M. D. D., et al. (2001) · Journal of Hepatology · doi:10.1016/s0168-8278(01)00192-1 · Cited by 186 · cited 1× · see citing works
“Nevertheless, secondary products of lipid peroxidation, such as malondialdehyde and 4-hydroxinonenal are utilized as oxidative stress markers in NASH patients [103], and Vitamin E, an antioxidant that suppresses lipid peroxidation, reduces serum ALT in NASH patients [104].”
BackgroundLinking Pathogenic Mechanisms of Alcoholic Liver Disease With Clinical Phenotypes
Nagy, L. E., Ding, W., Cresci, G., Saikia, P., & Shah, V. H. (2016) · Gastroenterology · doi:10.1053/j.gastro.2016.02.035 · Cited by 185 · cited 9× · see citing works
“Importantly, crossregulation by the effectors of different cell death pathways most likely influences liver inflammation in ALD.”
BackgroundInfluentialBrault, M., Olsen, T. M., Martinez, J., Stetson, D. B., & Oberst, A. (2018) · The Journal of Immunology · doi:10.4049/jimmunol.1701492 · Cited by 185 · cited 3× · see citing works
“Schock SN, Chandra NV, Sun Y, Irie T, Kitagawa Y, Gotoh B, et al. Induction of necroptotic cell death by viral activation of the RIG-I or STING pathway.”
BackgroundZargarian, S., Shlomovitz, I., Erlich, Z., Hourizadeh, A., Ofir-Birin, Y., Croker, B., Regev-Rudzki, N., Edry-Botzer, L., & Gerlic, M. (2017) · PLoS Biology · doi:10.1371/journal.pbio.2002711 · Cited by 181 · cited 1× · see citing works
“Finally, MLKL forms pore in the plasma membrane [16, 17], and increases permeability via the activation of A disintegrin and metalloproteinase (ADAM) proteases [18], Ca2+ influx by targeting the cation channel transient receptor potential melastatin related 7 (TRPM7) [19], and phosphatidylserine externalization [20].”
BackgroundBrumatti, G., Ma, C.-Y., Lalaoui, N., Nguyen, N.-Y. N., Navarro, M., Tanzer, M., Richmond, J., Ghisi, M., Salmon, J., Silke, N., et al. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aad3099 · Cited by 176 · cited 1× · see citing works
“Indeed, Emricasan has previously been shown to shift cell death from apoptosis towards necroptosis in acute myeloid leukemia cells treated with birinapant, a second mitochondrial derived activator of caspases mimetic, which enhances cancer cell apoptosis [145].”
BackgroundRIPK3 as a potential therapeutic target for Gaucher's disease
Vitner, E. B., Salomon, R., Farfel‐Becker, T., Meshcheriakova, A., Ali, M., Klein, A. D., Platt, F. M., Cox, T. M., & Futerman, A. H. (2014) · Nature Medicine · doi:10.1038/nm.3449 · Cited by 160 · cited 1× · see citing works
“In striking contrast, RIPK3-mediated necroptosis has been implicated in pathology of Gaucher’s disease [132].”
BackgroundGarcía–Tsao, G., Bosch, J., Kayali, Z., Harrison, S. A., Abdelmalek, M. F., Lawitz, E., Satapathy, S. K., Ghabril, M., Shiffman, M. L., Younes, Z. H., et al. (2019) · Journal of Hepatology · doi:10.1016/j.jhep.2019.12.010 · Cited by 158 · see citing works
Petrášek, J., Iracheta‐Vellve, A., Saha, B., Satishchandran, A., Kodys, K., Fitzgerald, K. A., Kurt‐Jones, E. A., & Szabó, G. (2015) · Journal of Leukocyte Biology · doi:10.1189/jlb.3ab1214-590r · Cited by 153 · cited 2× · see citing works
“Consistently, NLRP3 deficiency ameliorated alcohol-driven liver stetaosis and injury [120], while caspase-4/11 was upregulated in liver tissue from patients with alcoholic hepatitis and in mice [121].”
BackgroundMajdi, A., Aoudjehane, L., Ratziu, V., Islam, T., Afonso, M. B., Conti, F., Mestiri, T., Lagouge, M., Foufelle, F., Ballenghien, F., et al. (2019) · Journal of Hepatology · doi:10.1016/j.jhep.2019.11.008 · Cited by 147 · see citing works
Self-citationKang, Y. J., Bang, B., Han, K. H., Hong, L., Shim, E.-J., Ma, J., Lerner, R. A., & Otsuka, M. (2015) · Nature Communications · doi:10.1038/ncomms9371 · Cited by 144 · cited 1× · see citing works
“RIPK3-deficient natural killer cells showed impaired immune responses to tumours and liver inflammation [88].”
BackgroundBoaru, S. G., Borkham‐Kamphorst, E., Tihaa, L., Haas, U., & Weiskirchen, R. (2012) · Journal of Inflammation · doi:10.1186/1476-9255-9-49 · Cited by 142 · cited 1× · see citing works
“The NLRP3 inflammasome pathway is activated in hepatocytes in response to endotoxin challenge, a condition facilitated by alcohol intake [119].”
BackgroundInduction of necroptotic cell death by viral activation of the RIG-I or STING pathway
Schock, S., Chandra, N. V., Sun, Y., Irie, T., Kitagawa, Y., Gotoh, B., Coscoy, L., & Winoto, A. (2017) · Cell Death and Differentiation · doi:10.1038/cdd.2016.153 · Cited by 141 · cited 2× · see citing works
“The activation of necroptosis is not limited to DRs, and it can be triggered by multiple pathways, including toll-like receptors (e.g., TLR3 and TLR4) [26], nucleic acid sensors (e.g., Z-DNA-binding protein 1 [ZBP1, also known as DAI]) [27], retinoic acid inducible gene 1 protein (RIG1) [28], transmembrane protein 173…”
BackgroundReceptor Interacting Protein 3 Protects Mice from High Fat Diet-Induced Liver Injury
Roychowdhury, S., Mccullough, R. L., Sanz-García, C., Saikia, P., Alkhouri, N., Matloob, A., Pollard, K., McMullen, M. R., Croniger, C., & Nagy, L. E. (2016) · Hepatology · doi:10.1002/hep.28676 · Cited by 141 · cited 2× · see citing works
“Interestingly, RIPK3 deficiency protected from liver injury, inflammation and fibrosis in MCD-fed mice [74, 75], but exacerbated liver steatosis and apoptosis, as well as adipose tissue inflammation, insulin resistance and glucose intolerance induced by high-fat diet [79, 81].”
BackgroundProgrammed Cell Death and Inflammation: Winter Is Coming
Kolb, J. P., Oguin, T. H., Oberst, A., & Martinez, J. (2017) · Trends in Immunology · doi:10.1016/j.it.2017.06.009 · Cited by 131 · cited 1× · see citing works
“, ferroptosis), their chronic stimulation can lead to an excessive inflammation that may be detrimental and start damaging healthy cells, tissues, and organs [62].”
BackgroundNon-alcoholic fatty liver disease and the interface between primary and secondary care
Tsochatzis, E. A., & Newsome, P. N. (2018) · The Lancet. Gastroenterology & hepatology · doi:10.1016/s2468-1253(18)30077-3 · Cited by 130 · cited 1× · see citing works
“NAFLD is estimated to affect up to one-third of the general population worldwide [71].”
BackgroundVucur, M., Reisinger, F., Gautheron, J., Janssen, J., Roderburg, C., Cardenas, D. V., Kreggenwinkel, K., Koppe, C., Hammerich, L., Hakem, R., et al. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.07.035 · Cited by 127 · cited 1× · see citing works
“Other functions of RIPK3 in hepatocarcinogenesis have been recognized [85], and its involvement in inflammatory signalling independent of necroptosis and mediation of cell death should not be neglected [86, 87].”
BackgroundSelf-citationActivation of necroptosis in human and experimental cholestasis
Afonso, M. B., Rodrigues, P., Simão, A., Ofengeim, D., Carvalho, T., Amaral, J. D., Gaspar, M. M., Cortez-Pinto, H., Castro, R., Yuan, J., et al. (2016) · Cell Death and Disease · doi:10.1038/cddis.2016.280 · Cited by 126 · see citing works
Self-citationLiver Fibrosis in Alcoholic Liver Disease
Bataller, R., & Gao, B. (2015) · Seminars in liver disease (Print) · doi:10.1055/s-0035-1550054 · Cited by 114 · cited 1× · see citing works
“Alcohol-associated liver disease (ALD) is a major health problem worldwide and a significant source of liver injury, characterized by a wide spectrum of hepatic lesions from steatosis, steatohepatitis and fibrosis that may progress to cirrhosis and even hepatocellular carcinoma [112].”
BackgroundThe pseudokinase MLKL regulates hepatic insulin sensitivity independently of inflammation
Xu, H., Du, X., Liu, G., Huang, S., Du, W., Zou, S., Tang, D., Fan, C., Xie, Y., Wei, Y., et al. (2019) · Molecular Metabolism · doi:10.1016/j.molmet.2019.02.003 · Cited by 109 · cited 1× · see citing works
“High levels of core components of necroptosis were detected in liver, adipose tissue and muscle in diabetic mice, whereas targeting diabetic mice with RIPK1 inhibitors or depletion of MLKL prevented insulin resistance and glucose intolerance, despite no effect on inflammation [80].”
BackgroundCurrent translational potential and underlying molecular mechanisms of necroptosis
Molnár, T., Mázló, A., Tslaf, V., Szöllősi, A. G., Emri, G., & Koncz, G. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-2094-z · Cited by 107 · cited 2× · see citing works
“MLKL inhibitors are being developed such as necrosulfonamide, which binds to the N-terminal 4 helical bundle of MLKL to prevent necroptosis [146, 147].”
BackgroundmiRNA-21 ablation protects against liver injury and necroptosis in cholestasis
Afonso, M. B., Rodrigues, P., Simão, A., Gaspar, M. M., Carvalho, T., Borralho, P., Banales, J., Castro, R., & Rodrigues, C. (2018) · Cell Death and Differentiation · doi:10.1038/s41418-017-0019-x · Cited by 105 · cited 1× · see citing works
“Similarly, in common bile duct ligation hepatic injury, necroptosis was induced and contributed to fibrosis [82], although the effects of necroptosis inhibition on different hepatic fibrosis models are yet to be consistently determined.”
BackgroundSelf-citationActivation of cell-surface proteases promotes necroptosis, inflammation and cell migration
Cai, Z., Zhang, A., Choksi, S., Li, W., Li, T., Zhang, X.-M., & Liu, Z.-G. (2016) · Cell Research · doi:10.1038/cr.2016.87 · Cited by 103 · cited 1× · see citing works
“Finally, MLKL forms pore in the plasma membrane [16, 17], and increases permeability via the activation of A disintegrin and metalloproteinase (ADAM) proteases [18], Ca2+ influx by targeting the cation channel transient receptor potential melastatin related 7 (TRPM7) [19], and phosphatidylserine externalization [20].”
BackgroundThe necroptosis-inducing kinase RIPK3 dampens adipose tissue inflammation and glucose intolerance
Gautheron, J., Vucur, M., Schneider, A. T., Severi, I., Roderburg, C., Roy, S., Bartneck, M., Schrammen, P. L., Díaz, M. B., Ehling, J., et al. (2016) · Nature Communications · doi:10.1038/ncomms11869 · Cited by 102 · see citing works
Self-citationQuestions and controversies: the role of necroptosis in liver disease
Dara, L., Liu, Z., & Kaplowitz, N. (2016) · Cell Death Discovery · doi:10.1038/cddiscovery.2016.89 · Cited by 100 · cited 2× · see citing works
“First, there is vigorous controversy regarding the expression of RIPK3 by hepatocytes, but under basal conditions expression appears to be quite limited [135, 136].”
BackgroundNrf2 Knockdown Disrupts the Protective Effect of Curcumin on Alcohol-Induced Hepatocyte Necroptosis
Lu, C., Xu, W., Zhang, F., Shao, J., & Zheng, S. (2016) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.6b00562 · Cited by 97 · cited 1× · see citing works
“Other studies reported that ethanol-induced decrease of Nrf2 expression was abrogated by curcumin or gallic acid treatment, by suppressing RIPK3 and RIPK1 expression as well as DAMP release [116, 117].”
BackgroundWang, S., Ni, H., Dorko, K., Kumer, S. C., Schmitt, T. M., Nawabi, A. M., Komatsu, M., Huang, H., & Ding, W. (2016) · Oncotarget · doi:10.18632/oncotarget.6893 · Cited by 89 · cited 3× · see citing works
“Nevertheless, inhibition of RIP1 kinase activity blunted Gao-binge alcohol-induced hepatic inflammation but did not protect against chronic ethanol feeding-induced steatosis and liver injury, suggesting that alcohol-induced RIPK3-mediated necroptosis is independent of RIPK1 [114].”
BackgroundNeutrophil Necroptosis Is Triggered by Ligation of Adhesion Molecules following GM-CSF Priming
Wang, X., He, Z., Liu, H., Yousefi, S., & Simon, H. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1600051 · Cited by 86 · cited 1× · see citing works
“, Z-DNA-binding protein 1 [ZBP1, also known as DAI]) [27], retinoic acid inducible gene 1 protein (RIG1) [28], transmembrane protein 173 (TMEM173, also known as STING) [29], and adhesion receptors [30].”
BackgroundRay, C., & Pickup, D. (1996) · Virology · doi:10.1006/viro.1996.0128 · Cited by 86 · cited 1× · see citing works
“the expression of the viral cytokine response modifier A (CrmA), a caspase inhibitor [5].”
BackgroundIron-Induced Liver Injury: A Critical Reappraisal
Bloomer, S. A., & Brown, K. E. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20092132 · Cited by 84 · cited 1× · see citing works
“Iron-induced liver damage is likely potentiated by coexisting inflammation, which culminates with hepatocyte cell death and drives fibrogenesis [127].”
BackgroundNecrosis-dependent and independent signaling of the RIP kinases in inflammation
Moriwaki, K., & Chan, F. K.-M. (2013) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2013.12.013 · Cited by 83 · cited 1× · see citing works
“Other functions of RIPK3 in hepatocarcinogenesis have been recognized [85], and its involvement in inflammatory signalling independent of necroptosis and mediation of cell death should not be neglected [86, 87].”
BackgroundValenti, L. V. C., Moscatiello, S., Vanni, E., Fracanzani, A. L., Bugianesi, E., Fargion, S. R., & Marchesini, G. (2010) · QJM · doi:10.1093/qjmed/hcq170 · Cited by 82 · cited 5× · see citing works
“Ablation of Ripk3 resulted in fewer CD68-positive Kupffer cells and decreased ALT activity, suggesting that hepatocyte injury was also attenuated.”
BackgroundInfluentialAizawa, S., Brar, G., & Tsukamoto, H. (2019) · Gut and Liver · doi:10.5009/gnl18486 · Cited by 77 · see citing works
Ni, H.-M., Chao, X.-J., Kaseff, J., Deng, F.-Y., Wang, S.-G., Shi, Y.-H., Li, T.-G., Ding, W.-X., & Jaeschke, H. (2019) · American Journal of Pathology · doi:10.1016/j.ajpath.2019.03.010 · Cited by 68 · cited 1× · see citing works
“RIPK3MLKL-mediated necroptosis contributed also to ischemia reperfusion injury of steatotic livers [83].”
BackgroundZhou, Z., Ye, T.-J., Bonavita, G., Daniels, M., Kainrad, N., Jogasuria, A. P., & You, M. (2019) · Hepatology Communications · doi:10.1002/hep4.1333 · Cited by 64 · see citing works
Hanna-Addams, S., Liu, S., Liu, H., Chen, S., & Wang, Z. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1917112117 · Cited by 58 · see citing works
Necroptosis in Niemann–Pick disease, type C1: a potential therapeutic target
Cougnoux, A., Cluzeau, C. V. M., Mitra, S., Li, R., Williams, I. M., Burkert, K. R., Xu, X., Wassif, C. A., Zheng, W., & Porter, F. D. (2016) · Cell Death and Disease · doi:10.1038/cddis.2016.16 · Cited by 58 · cited 2× · see citing works
“Nevertheless, corroborating the role of alternative RCD sub-routines, cellular death of NPC1 fibroblasts was not mitigated by treatment with caspase inhibitors [129] or following neuronal overexpression of Bcl-2 [130].”
BackgroundStudies on neuronal death in the mouse model of Niemann‐Pick C disease
Erickson, R., & Bernard, O. (2002) · Journal of Neuroscience Research · doi:10.1002/jnr.10257 · Cited by 55 · cited 1× · see citing works
“Nevertheless, corroborating the role of alternative RCD sub-routines, cellular death of NPC1 fibroblasts was not mitigated by treatment with caspase inhibitors [129] or following neuronal overexpression of Bcl-2 [130].”
BackgroundGasdermin D protects against noninfectious liver injury by regulating apoptosis and necroptosis
Yang, C., Sun, P., Deng, M., Loughran, P., Li, W., Yi, Z., Li, S., Zhang, X., Fan, J., Billiar, T. R., et al. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-1719-6 · Cited by 54 · cited 1× · see citing works
“Interestingly, in shock models of liver injury, GSDMD germ line deficient mice display increased caspase-8 activation and apoptosis in the liver [141].”
BackgroundSaeed, W., Jun, D., Jang, K., Oh, J.-H., Chae, Y., Lee, J.-S., Koh, D., & Kang, H. (2019) · Journal of Gastroenterology and Hepatology · doi:10.1111/jgh.14740 · Cited by 50 · cited 1× · see citing works
“Similarly, MLKL pharmacological inhibition decreased hepatic de novo fat synthesis and chemokine ligand expression in NASH [91].”
BackgroundThe Receptor Interacting Protein Kinases in the Liver
Dara, L. (2018) · Seminars in Liver Disease · doi:10.1055/s-0038-1629924 · Cited by 43 · see citing works
The inflammasome in alcoholic hepatitis: its relationship with Mallory-Denk body formation
Peng, Y., French, B., Tillman, B., Morgan, T., & French, S. (2014) · Experimental and molecular pathology (Print) · doi:10.1016/j.yexmp.2014.08.006 · Cited by 43 · cited 1× · see citing works
“Caspase-1 was also activated in hepatocytes of patients with alcoholic hepatitis [123].”
BackgroundGallic acid protects against ethanol-induced hepatocyte necroptosis via an NRF2-dependent mechanism.
Zhou, Y., Jin, H., Wu, Y., Chen, L., Bao, X.-F., & Lu, C.-F. (2019) · Toxicology in Vitro · doi:10.1016/j.tiv.2019.03.008 · Cited by 40 · cited 1× · see citing works
“Other studies reported that ethanol-induced decrease of Nrf2 expression was abrogated by curcumin or gallic acid treatment, by suppressing RIPK3 and RIPK1 expression as well as DAMP release [116, 117].”
BackgroundKöhn-Gaone, J., Dwyer, B. J., Grzelak, C. A., Miller, G. C., Shackel, N., Ramm, G., Mccaughan, G., Elsegood, C., Olynyk, J., & Tirnitz-Parker, J. E. E. (2016) · American Journal of Pathology · doi:10.1016/j.ajpath.2016.03.005 · Cited by 37 · cited 1× · see citing works
“In a recent study, ferroptosis inhibitors, trolox and deferiprone, suppressed necrotic cell death, infiltration of inflammatory cells, and inflammatory cytokine expression in the onset of steatohepatitis in the choline-deficient, ethionine-supplemented (CDE) diet model [108], in which hepatic cell death is an early ev…”
BackgroundZhang, Z., Xie, G.-M., Liang, L.-H., Liu, H., Pan, J., Cheng, H., Wang, H., Qu, A.-J., & Wang, Y. (2018) · Journal of Immunological Research · doi:10.1155/2018/1509851 · Cited by 37 · see citing works
Necroptosis in Nonalcoholic Steatohepatitis
Gautheron, J., Vucur, M., & Luedde, T. (2015) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2015.02.001 · Cited by 35 · see citing works
Self-citationRescue from a fiery death: A therapeutic endeavor
Kayagaki, N., & Dixit, V. (2019) · Science · doi:10.1126/science.aaw1177 · Cited by 35 · cited 2× · see citing works
“Cleave of GSDMD occurs via a canonical inflammasome caspase-1 dependent mechanism, a non-canonical inflammasome pathway involving caspases 4, 5 or 11 [139], or in an inflammasome-independent caspase-8 mediated pathway [140].”
BackgroundKrishna-Subramanian, S., Singer, S., Armaka, M., Banales, J., Holzer, K., Schirmacher, P., Walczak, H., Kollias, G., Pasparakis, M., & Kondylis, V. (2019) · Cell Death and Differentiation · doi:10.1038/s41418-019-0330-9 · Cited by 32 · cited 3× · see citing works
“Third, caspase-8 limits necroptosis by proteolytically cleaving RIPK1 [138], and the genetic absence of caspase-8 in hepatocytes does not trigger widespread necroptosis [134].”
BackgroundCougnoux, A., Clifford, S., Salman, A., Ng, S.-L., Bertin, J., & Porter, F. (2018) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2018.10.009 · Cited by 29 · see citing works
Processes exacerbating apoptosis in non-alcoholic steatohepatitis
Afonso, M. B., Castro, R. E., & Rodrigues, C. M. P. (2019) · Clinical Science · doi:10.1042/cs20190068 · Cited by 23 · cited 1× · see citing works
“Indeed, lipotoxicity, oxidative stress, organelle dysfunction and inflammatory response exacerbate ballooning and increase hepatocyte cell death [73].”
BackgroundSelf-citationUnderstanding allosteric interactions in hMLKL protein that modulate necroptosis and its inhibition
Bansal, N., Sciabola, S., & Bhisetti, G. (2019) · Scientific Reports · doi:10.1038/s41598-019-53078-5 · Cited by 20 · cited 1× · see citing works
“MLKL inhibitors are being developed such as necrosulfonamide, which binds to the N-terminal 4 helical bundle of MLKL to prevent necroptosis [146, 147].”
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Sorted by citations
The multifaceted role of ferroptosis in liver disease
Chen, J., Li, X., Ge, C., Min, J., & Wang, F. (2022) · Cell Death and Differentiation · doi:10.1038/s41418-022-00941-0 · Cited by 679 · see citing works
How does hepatic lipid accumulation lead to lipotoxicity in non-alcoholic fatty liver disease?
Geng, Y., Faber, K., de Meijer, V. D., Blokzijl, H., & Moshage, H. (2021) · Hepatology International · doi:10.1007/s12072-020-10121-2 · Cited by 392 · see citing works
Oxidative stress and regulated cell death in Parkinson’s disease
Dionísio, P. A., Amaral, J. D., & Rodrigues, C. M. P. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101263 · Cited by 436 · see citing works
Self-citationXu, X., Poulsen, K. L., Wu, L., Liu, S., Miyata, T., Song, Q., Wei, Q., Zhao, C., Lin, C., & Yang, J. B. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01119-3 · Cited by 370 · see citing works
“Multiple types of cell death, including apoptosis, necroptosis, pyroptosis, and ferroptosis, as well as autophagy, are associated with the development of NAFL/ NASH.(72,293,294) Among targeting different formats of cell death, inhibition of apoptosis has achieved promising results, here we focus on anti-apoptosis agen…”
BackgroundInfluentialFerroptosis in Liver Diseases: An Overview
Capelletti, M. M., Manceau, H., Puy, H., & Peoc’h, K. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21144908 · Cited by 364 · see citing works
“New studies focused on the molecular basis of ferroptosis could help in deciphering the existing connections between the single components of the metabolic pathway.”
BackgroundInfluentialLiu, Z., Wang, M., Wang, X., Bu, Q., Wang, Q., Su, W., Li, L., Zhou, H., & Lü, L. (2022) · Redox Biology · doi:10.1016/j.redox.2022.102305 · Cited by 353 · see citing works
“Increased hepatocyte pyroptosis contributes to the pathology of acute and chronic liver diseases [35,36].”
BackgroundUpdated mechanisms of MASLD pathogenesis
Li, Y., Yang, P., Ye, J., Xu, Q., Wu, J., & Wang, Y. (2024) · Lipids in Health and Disease · doi:10.1186/s12944-024-02108-x · Cited by 333 · see citing works
“In terms of cellular morphology, ferroptosis is characterized by smaller mitochondrial volume, increased membrane density, and a lower number of cristae, along with insignificant changes in the nucleus [93].”
BackgroundCell Death in Liver Diseases: A Review
Shojaie, L., Iorga, A., & Dara, L. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21249682 · Cited by 299 · see citing works
“Further research using GSDMD KO models with other dietary models is needed to study the role of pyroptosis in NAFLD/NASH [47,89,136].”
MethodInfluentialTNF in the liver: targeting a central player in inflammation
Tiegs, G., & Horst, A. K. (2022) · Seminars in Immunopathology · doi:10.1007/s00281-022-00910-2 · Cited by 231 · see citing works
Insights into N6-methyladenosine and programmed cell death in cancer
Liu, L., Li, H., Hu, D., Wang, Y., Shao, W., Zhong, J., Yang, S., Liu, J., & Zhang, J. (2022) · Molecular Cancer · doi:10.1186/s12943-022-01508-w · Cited by 218 · see citing works
Immunological mechanisms and therapeutic targets of fatty liver diseases
Wang, H., Mehal, W. Z., Nagy, L. E., & Rotman, Y. (2020) · Cellular and Molecular Immunology · doi:10.1038/s41423-020-00579-3 · Cited by 222 · see citing works
The intersection between alcohol-related liver disease and nonalcoholic fatty liver disease
Díaz, L. A., Arab, J. P., Louvet, A., Bataller, R., & Arrese, M. (2023) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-023-00822-y · Cited by 207 · see citing works
“Both metabolic dysfunction and chronic alcohol exposure induce multiple forms of cellular stress that lead to cell injury and death, which are key drivers of disease progression 97 .”
BackgroundLuci, C., Bourinet, M., Leclère, P. S., Anty, R., & Gual, P. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.597648 · Cited by 195 · see citing works
“Targeting the Liver Injury (Hepatocyte Death) As previously described, different types of hepatocyte death have been associated with NAFLD progression and drive hepatic inflammation (40).”
BackgroundYang, Y. M., Cho, Y. E., & Hwang, S. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23020774 · Cited by 203 · see citing works
“In the liver, ferroptosis generates ROS and depletes glutathione levels [78,79].”
BackgroundRoles of RIPK3 in necroptosis, cell signaling, and disease
Morgan, M. J., & Kim, Y. (2022) · Experimental & Molecular Medicine · doi:10.1038/s12276-022-00868-z · Cited by 189 · see citing works
Tillman, E. J., & Rolph, T. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.601290 · Cited by 209 · see citing works
Lan, T., Yu, Y., Zhang, J., Li, H.-N., Weng, Q., Jiang, S., Tian, S., Xu, T., Hu, S., Yang, G., et al. (2021) · Hepatology · doi:10.1002/hep.31749 · Cited by 176 · see citing works
“Lipotoxicity eventually leads to hepatocyte injury or even death (24); thus, serum ALT and AST levels were measured.”
BackgroundXiao, Y., Zhao, C., Tai, Y., Li, B., Lan, T., Lai, E., Dai, W., Guo, Y., Gan, C., Kostallari, E., et al. (2023) · Redox Biology · doi:10.1016/j.redox.2023.102691 · Cited by 182 · see citing works
Liu, J., Zhou, J., Luan, Y., Li, X., Meng, X., Liao, W., Tang, J., & Wang, Z. (2024) · Cell Communication and Signaling · doi:10.1186/s12964-023-01466-w · Cited by 159 · see citing works
“GSDMD-mediated hepatocyte pyroptosis contributes to accelerated pathogenesis in acute and chronic liver disease [156–159].”
BackgroundNon-alcoholic Fatty Liver Disease and Alcohol-Related Liver Disease: Two Intertwined Entities
Idalsoaga, F., Kulkarni, A. V., Mousa, O. Y., Arrese, M., & Arab, J. P. (2020) · Frontiers in Medicine · doi:10.3389/fmed.2020.00448 · Cited by 136 · see citing works
Vachliotis, I. D., & Polyzos, S. (2023) · Current Obesity Reports · doi:10.1007/s13679-023-00519-y · Cited by 115 · see citing works
The role of bile acids in cholestatic liver injury
Cai, S.-Y., & Boyer, J. (2020) · Annals of Translational Medicine · doi:10.21037/atm-20-5110 · Cited by 110 · see citing works
“Necroptosis is a form of regulated necrotic cell death (59,60).”
BackgroundROS/RNS as molecular signatures of chronic liver diseases
Che, Z., Zhou, Z., Li, S.-Q., Gao, L., Xiao, J., & Wong, N.-K. (2023) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2023.08.001 · Cited by 110 · see citing works
Xu, S.-X., Chen, Y.-E., Miao, J., Li, Y.-H., Liu, J., Zhang, J., Liang, J., Chen, S.-X., & Hou, S.-Z. (2024) · Phytomedicine · doi:10.1016/j.phymed.2024.155465 · Cited by 101 · see citing works
Nuclear receptors linking metabolism, inflammation, and fibrosis in nonalcoholic fatty liver disease
Puengel, T., Liu, H., Guillot, A., Heymann, F., Tacke, F., & Peiseler, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23052668 · Cited by 95 · see citing works
“In recent years, a better understanding of cell death mechanisms has expanded the number of known processes involved in metabolic liver diseases, from apoptosis to mitochondrial permeability transition (MPT)-driven necrosis, and necroptosis, autophagic apoptosis, and pyroptosis [38].”
BackgroundGuo, T., Yan, W., Cui, X., Liu, N., Wei, X., Sun, Y., Fan, K.-X., Liu, J., Zhu, Y.-Y., Wang, Z., et al. (2023) · Molecular Medicine · doi:10.1186/s10020-023-00721-7 · Cited by 93 · see citing works
“In recent years, accumulating evidence indicates that ferroptosis is involved in the progression of NAFLD (Gautheron et al. 2020; Wang et al. 2022b).”
BackgroundSalvianolic acid B attenuates liver fibrosis by targeting Ecm1 and inhibiting hepatocyte ferroptosis
Fu, Y.-D., Zhou, X., Wang, L., Fan, W.-G., Gao, S.-Q., Zhang, D.-D., Ling, Z., Zhang, Y.-G., Ma, L.-Y., Bai, F., et al. (2024) · Redox Biology · doi:10.1016/j.redox.2024.103029 · Cited by 91 · see citing works
“In recent years, increasing research has focused on the contribution of hepatocytes and extracellular matrix to the progression of liver fibrosis [7 – 9].”
BackgroundZhuge, A., Li, S., Han, S., Yuan, Y., Shen, J., Wu, W., Wang, K., Xia, J., Wang, Q., Gu, Y., et al. (2024) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2024.10.010 · Cited by 94 · see citing works
Why Do So Many Nonalcoholic Steatohepatitis Trials Fail?
Ratziu, V., & Friedman, S. L. (2023) · Gastroenterology · doi:10.1053/j.gastro.2020.05.046 · Cited by 88 · see citing works
Shi, H., Wang, X., Li, F., Gerlach, B. D., Yurdagul, A., Moore, M. P., Zeldin, S., Zhang, H., Cai, B., Zheng, Z., et al. (2022) · Science Translational Medicine · doi:10.1126/scitranslmed.abp8309 · Cited by 85 · see citing works
“One theory holds that molecules leaking from uncleared dead cells, such as damage-associated molecular patterns, might activate hepatic macrophages and hepatic stellate cells (HSCs), triggering hepatic inflammation and fibrosis (11, 12).”
BackgroundIron, Oxidative Stress, and Metabolic Dysfunction—Associated Steatotic Liver Disease
Gensluckner, S., Wernly, B., Datz, C., & Aigner, E. S. (2024) · Antioxidants · doi:10.3390/antiox13020208 · Cited by 81 · see citing works
“In MASLD, different cell death mechanisms like necroptosis, pyroptosis, and ferroptosis contribute to disease progression [49].”
BackgroundHepatic Stellate Cell-Immune Interactions in NASH
Carter, J. K., & Friedman, S. L. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.867940 · Cited by 79 · see citing works
“These pathways involve rapid membrane permeabilization and release of cytoplasmic contents, triggering a stronger immune response than apoptosis (12).”
BackgroundPeleman, C., Francque, S., & Berghe, T. V. (2024) · EBioMedicine · doi:10.1016/j.ebiom.2024.105088 · Cited by 86 · see citing works
Ferroptosis and metabolic dysfunction‐associated fatty liver disease: Is there a link?
Feng, G., Byrne, C. D., Targher, G., Wang, F.-D., & Zheng, M. (2022) · Liver international (Print) · doi:10.1111/liv.15163 · Cited by 77 · see citing works
Wang, Y., Zhao, Y., Wang, Z.-C., Sun, R., Zou, B., Li, R., Liu, D., Lin, M., Zhou, J.-J., Ning, S.-L., et al. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.652782 · Cited by 73 · see citing works
“Pyroptosis is a newly identified type of programmed cell death (PCD) characterized by pore formation in the plasma membrane, swelling, cell rupture, and proinflammatory factor release (11, 12).”
BackgroundChen, C., Liu, J., Lin, X., Xiang, A., Ye, Q., Guo, J., Tao, R., Xu, J., & Hu, S. (2024) · Cell Death Discovery · doi:10.1038/s41420-024-01958-9 · Cited by 70 · see citing works
“Unlikeapoptotic cell death, lytic forms of cell death, such as pyroptosis and ferroptosis, lead to membrane permeabilization and cell lysis and the subsequent release of intracellular components and in fl ammatory cytokines [155, 156].”
BackgroundChen, T.-X., Meng, Y., Zhou, Z.-H., Li, H., Wan, L.-F., Kang, A., Guo, W., Ren, K., Song, X., Chen, Y., et al. (2023) · Cell Death and Differentiation · doi:10.1038/s41418-023-01183-4 · Cited by 66 · see citing works
“Pyroptosis may be activated by lipid toxicity, inflammation, and oxidative stress during NAFLD development [20, 21].”
BackgroundPyroptosis: Mechanisms and Links with Fibrosis
Song, Z., Gong, Q., & Guo, J. (2021) · Cells · doi:10.3390/cells10123509 · Cited by 68 · see citing works
“A large number of studies have shown that pyroptosis plays an important role in the process of liver fibrosis [29,48].”
BackgroundTargeting cell death in NAFLD: mechanisms and targeted therapies
Xu, H., Wan, S., An, Y., Wu, Q., Xing, Y.-H., Deng, C.-H., Zhang, P., Long, Y., Xu, B.-T., & Jiang, Z. (2024) · Cell Death Discovery · doi:10.1038/s41420-024-02168-z · Cited by 70 · see citing works
“Based on accumulating evidence, RCD is closely related to the initiation and progression of NAFLD [6, 7].”
BackgroundXue, M.-L., Tian, Y., Sui, Y., Zhao, H., Gao, H.-Q., Liang, H.-C., Qiu, X.-Z., Sun, Z.-Y., Zhang, Y., & Qin, Y.-M. (2022) · Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · doi:10.1016/j.biopha.2022.113402 · Cited by 64 · see citing works
Inflammatory signaling in NASH driven by hepatocyte mitochondrial dysfunctions
Myint, M., Oppedisano, F., De Giorgi, V., Kim, B.-M., Marincola, F. M., Alter, H. J., & Nesci, S. (2023) · Journal of Translational Medicine · doi:10.1186/s12967-023-04627-0 · Cited by 61 · see citing works
“Hepatocyte RCD, including apoptosis and lytic forms of hepatocellular death, such as necrosis, necroptosis, pyroptosis and ferroptosis [85], drives activation of Kupffer cells and other non-parenchymal cells, such as HSCs.”
BackgroundInaba, Y., Hashiuchi, E., Watanabe, H., Kimura, K., Oshima, Y., Tsuchiya, K., Murai, S., Takahashi, C., Matsumoto, M., Kitajima, S., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-35804-w · Cited by 60 · see citing works
Liu, B., Yi, W., Mao, X., Yang, L., & Rao, C. (2021) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00614.2020 · Cited by 63 · see citing works
Cell Death in Hepatocellular Carcinoma: Pathogenesis and Therapeutic Opportunities
García‐Pras, E., Fernández‐Iglesias, A., Gracia‐Sancho, J., & Pérez‐del‐Pulgar, S. (2021) · Cancers · doi:10.3390/cancers14010048 · Cited by 60 · see citing works
“Pyroptosis is a highly proinflammatory cell death mode, predominantly dependent on caspase-1 and caspase 4/5/11 [15,46].”
BackgroundTumor necrosis factor-α signaling in nonalcoholic steatohepatitis and targeted therapies
Lü, S., Wang, Y., & Liu, J. (2021) · Journal of genetics and genomics/Journal of Genetics and Genomics · doi:10.1016/j.jgg.2021.09.009 · Cited by 75 · see citing works
Regulation of Ferroptosis Pathway by Ubiquitination
Wang, X., Wang, Y., Li, Z., Qin, J., & Wang, P. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.699304 · Cited by 54 · see citing works
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“Log-rank test, two-way ANOVA with post-hoc test. importance is dif fi cult to study [6, 7].”
MethodThe liver as a central "hub" of the immune system: pathophysiological implications
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“Hepatocyte injury and death are known to initiate ACLF [1 – 5, 35 ] ; however , whether and how cell death occurs and affects HBV-related ACLF progression remain unclear.”
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“Primarily, regulated cell death (RCD) in metabolic liver disease is comprised of apoptosis, necroptosis, pyroptosis and ferroptosis [20,21].”
BackgroundZhang, J., Xie, H.-N., Yao, J., Jin, W., Pan, H., Pan, Z.-Q., Xie, D.-Y., & Xie, D.-H. (2022) · Human Cell · doi:10.1007/s13577-022-00820-3 · Cited by 50 · see citing works
“A previous study indicated that ferroptosis played a critical role for the development NAFLD [41].”
BackgroundRIPK3 dampens mitochondrial bioenergetics and lipid droplet dynamics in metabolic liver disease
Afonso, M. B., Islam, T., Magusto, J., Amorim, R., Lenoir, V., Simões, R. F., Teixeira, J., Silva, L. C., Wendum, D., Jéru, I., et al. (2022) · Hepatology · doi:10.1002/hep.32756 · Cited by 56 · see citing works
Self-citationHa, Y., Jeong, I., & Kim, T. H. (2022) · Biomedicines · doi:10.3390/biomedicines10102530 · Cited by 47 · see citing works
Ferroptosis in non-alcoholic liver disease: Molecular mechanisms and therapeutic implications
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“It is commonly accepted that ferroptosis, as a modality of cell death, is usually concomitant with compromised cellular membrane and the release of cellular constituents, which can recruit a number of immune cells, further eliciting strong inflammatory responses (8).”
BackgroundInfluentialMiyata, T., Wu, X.-Q., Fan, X., Huang, E., Sanz-García, C., Cajigas-DuRoss, C., Roychowdhury, S., Bellar, A., McMullen, M., Dasarathy, J., et al. (2021) · JCI Insight · doi:10.1172/jci.insight.140180 · Cited by 44 · see citing works
“Discussion Multiple pathways of regulated cell death are implicated in the progression of metabolic liver diseases; however, the contributions of individual pathways of regulated cell death to specific liver diseases are not well understood (31).”
MetALD: Clinical aspects, pathophysiology and treatment
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“82”
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“Different types of cell death occur simultaneously in various liver diseases, including liver injury, metabolic liver disease, and cancer [3, 4].”
BackgroundWu, C., Bian, Y., Lu, B., Wang, D., Azami, N. L. B., Wei, G., Ma, F., & Sun, M. (2022) · Journal of Translational Medicine · doi:10.1186/s12967-022-03495-4 · Cited by 43 · see citing works
“DAMPs released from injurious hepatocytes produced inflammatory factors by activating Kuffer cells, so as to further promoted and maintained the activation of hepatic stellate cells (HSCs), and finally lead to the continuous secretion of collagen and fibers by HSCs, thus forming hepatic fibrosis and even cirrhosis [45…”
BackgroundZhang, H.-J., Zhou, L., Zhou, Y.-H., Wang, L.-L., Jiang, W.-L., Liu, L., Yue, S., Zheng, P.-D., & Liu, H.-G. (2021) · Life Science · doi:10.1016/j.lfs.2021.119963 · Cited by 41 · see citing works
Oleanolic acid inhibits mercury chloride induced-liver ferroptosis by regulating ROS/iron overload.
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Yuan, Y., Li, Y., Li, L., Liu, H., Pang, Y., & Yan, H. (2022) · Toxicology Letters · doi:10.1016/j.toxlet.2022.08.007 · Cited by 39 · see citing works
Harnessing ferroptosis for precision oncology: challenges and prospects
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“…injuries and inflammatory diseases [164–166], including rheumatoid arthritis [167], inflammatory bowel disease [168, 169], metabolic dysfunction-associated steatotic liver disease (MASLD) [170], and liver fibrosis [171], driven by advances in biomarker discovery and precision medicine.”
Liver fibrosis is a common pathological change in the liver of dairy cows with fatty liver.
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Iron as a therapeutic target in chronic liver disease
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Physiological Effects of Ferroptosis on Organ Fibrosis
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“[44]”
Ferroptosis: Shedding Light on Mechanisms and Therapeutic Opportunities in Liver Diseases
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Research mechanisms of and pharmaceutical treatments for ferroptosis in liver diseases
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Pathophysiological Mechanisms in Non-Alcoholic Fatty Liver Disease: From Drivers to Targets
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“This enzyme might directly cause hepatocyte injury, and activate HSCs, and its deletion in HFD-induced NASH decreases liver inflammation and fibrosis [134,135].”
BackgroundInfluentialEfferocytosis in liver disease
Shi, H., Moore, M. P., Wang, X., & Tabas, I. (2024) · JHEP Reports · doi:10.1016/j.jhepr.2023.100960 · Cited by 30 · see citing works
“Multiple forms of liver cell death, including necrosis, apoptosis, necroptosis, pyroptosis, and ferroptosis, have been reported in various types of liver disease, 5 – 8, 22”
BackgroundThe key players of inflammasomes and pyroptosis in sepsis-induced pathogenesis and organ dysfunction
Zhu, L., Hu, M., Xu, H., Xu, H., Ren, B., Xu, R., Guo, M., Chen, H., Zhang, D., & Fang, H. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1586364 · Cited by 30 · see citing works
Kinases control of regulated cell death revealing druggable targets for Parkinson’s disease
Mansour, H. M., Mohamed, A. F., El-Khatib, A. S., & Khattab, M. M. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2022.101841 · Cited by 44 · see citing works
Elucidating cuproptosis in metabolic dysfunction-associated steatotic liver disease
Li, Y., Qi, P., Song, S., Wang, Y., Wang, H., Cao, P., Liu, Y., & Wang, Y. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.116585 · Cited by 27 · see citing works
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Recent progress in the effect of ferroptosis of HSCs on the development of liver fibrosis
Tang, R., Luo, J., Zhu, X., Miao, P.-Y., Tang, H., Jian, Y., Ruan, S.-B., Ling, F.-Q., & Tang, M.-X. (2023) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2023.1258870 · Cited by 27 · see citing works
“…iron overload induced ferroptosis, they release ROS and proin fl ammatory factors, transmit risk signals to surrounding cells including in fl ammatory cells and HSCs, and induce chronic in fl ammation and directly or indirectly induce the activation and proliferation of HSCs (Gautheron et al., 2020).”
BackgroundMori fructus aqueous extracts attenuates liver injury by inhibiting ferroptosis via the Nrf2 pathway
Wei, Y., Gao, C., Wang, H.-R., Zhang, Y.-N., Gu, J.-H., Zhang, X.-Y., Gong, X.-H., & Hao, Z.-H. (2023) · Journal of Animal Science and Biotechnology · doi:10.1186/s40104-023-00845-0 · Cited by 27 · see citing works
Cheng, Z., Chu, H., Seki, E., Lin, R., & Yang, L. (2024) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2024.1431921 · Cited by 30 · see citing works
“The morphological features of ferroptosis encompass mitochondrial atrophy, decreased or obliterated mitochondrial cristae, as well as cellular membrane rupture (Gautheron et al., 2020).”
BackgroundInfluentialShi, J., Liu, Y., Wang, Y., Gao, R., Wang, Y., & Liu, J. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1194343 · Cited by 25 · see citing works
“In general, previous studies have shown that iron overload is an important factor driving alcohol-induced liver injury (Chu et al., 2019; Gautheron et al., 2020; Chen et al., 2021b).”
BackgroundThe role of MLKL in Hepatic Ischemia-Reperfusion Injury of Alcoholic Steatotic Livers
Chen, H., McKeen, T., Chao, X.-J., Chen, A., Deng, F.-Y., Jaeschke, H., Ding, W.-X., & Ni, H.-M. (2022) · International Journal on Biological Sciences · doi:10.7150/ijbs.67533 · Cited by 26 · see citing works
“While excessive pyroptosis causes various inflammatory diseases like sepsis, pyroptosis also gains more attention in the pathogenesis of ALD and IR injury [52, 53].”
BackgroundRao, Y., Li, C., Hu, Y., Xu, Y., Song, B., Guo, S., Jiang, Z., Zhao, D., Chen, S.-B., Tan, J., et al. (2021) · British Journal of Pharmacology · doi:10.1111/bph.15727 · Cited by 27 · see citing works
“We also identified many novel HSF1-associated transcripts involved in autophagy and ferroptosis, such as ATG10, PARK2 and SFXN1 (Table S1), which have also been reported to be involved in the development of MAFLD/NASH in vivo (Gautheron et al., 2020; Tanaka et al., 2016).”
BackgroundAdvancements in the Alcohol-Associated Liver Disease Model
Zhu, L., Li, H.-D., Xu, J., Li, J., Cheng, M., Meng, X., Huang, C., & Li, J. (2022) · Biomolecules · doi:10.3390/biom12081035 · Cited by 30 · see citing works
“In addition, long-term alcohol consumption increases the serum ferritin concentration and transporter saturation, thereby increasing hepatic iron storage and the production of reactive oxygen species and causing local inflammation [19,40].”
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“In the process, GSH is consumed, GXP4 activity is inhibited, lipid peroxidation occurs, inducing cell ferroptosis, and exacerbating ALD development [34, 35].”
BackgroundMesenchymal stem cells and ferroptosis: Clinical opportunities and challenges
Cui, M., Chen, F., Shao, L., Wei, C., Zhang, W., Sun, W., & Wang, J. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e25251 · Cited by 22 · see citing works
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“These lead to the release of DAMPs, which in turn induce inflammatory responses and consequential secondary injury [ 98].”
BackgroundSitbon, A., Delmotte, P.-R., Pistorio, V., Halter, S., Gallet, J., Gautheron, J., & Monsel, A. (2024) · Journal of Translational Medicine · doi:10.1186/s12967-024-05282-9 · Cited by 24 · see citing works
“Pyroptosis serves as another modality of programmed cell death marked by the expulsion of pro-inflammatory substances, relevant in hepatic inflammation and damage [28].”
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Unravelling the Role of PANoptosis in Liver Diseases: Mechanisms and Therapeutic Implications
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“Many studies have highlighted the critical role of the ferroptosis of hepatocytes in orchestrating a cascade of immune responses during endotoxemia [8–10].”
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Contribution of classification based on ferroptosis-related genes to the heterogeneity of MAFLD
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“Different types of cell death, such as necroptosis, pyroptosis and ferroptosis, coexist as metabolic liver disease progresses [4].”
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AT1 receptor autoantibodies mediate effects of metabolic syndrome on dopaminergic vulnerability.
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Lipid Peroxidation in Ferroptosis and Association with Nonalcoholic Fatty Liver Disease
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“Evidence suggests ferroptosis is tightly associated with lipid peroxidation (LPO) in NAFLD and can therefore be an important target for preventing and treating NAFLD [8].”
BackgroundMicroRNAs and Nonalcoholic Steatohepatitis: A Review
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“…involvement of miRNAs in various pathological conditions and the formation of diseases via post-transcriptional regulation [31]. miRNA– disease relationships have been most studied in the fields of cancer and infectious diseases for which nucleic acid medicine therapies have already been attempted.”
BackgroundExosomal microRNAs and Progression of Nonalcoholic Steatohepatitis (NASH)
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“Lipotoxicity in hepatocytes has been recognized as the fundamental feature of NASH [1].”
BackgroundRegulated lytic cell death in breast cancer
Liu, M., Wang, L., Xia, X., Wu, Y., Zhu, C., Duan, M., Wei, X., Hu, J., & Lei, L. (2021) · Cell Biology International · doi:10.1002/cbin.11705 · Cited by 19 · see citing works
“Importantly, these new RCD pathways may exist concurrently in pathological conditions, and there are several common overlapped mechanisms that can serve as ‘backup’ death mechanisms to ensure biological homoeostasis when the threshold that causes cell death is reached (Gautheron et al., 2020).”
BackgroundThe role of RIPK3 in liver mitochondria bioenergetics and function
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Self-citation
- Authors
- Gautheron, J., Gores, G. J., & Rodrigues, C. M. P.
- Affiliations
- Inserm (FR)
- Mayo Clinic (US)
- University of Lisbon (PT)
- Corresponding author
- Rodrigues, Cecília M.P.
- Venue
- Journal of Hepatology
- Publisher
- Elsevier BV
- Published
- 2020-08
- Volume
- 73
- Issue
- 2
- Pages
- 394-408
- ISSN
- 0168-8278 (ISSN-L)
- PMC
- PMC7371520
- OpenAlex
- W3016394009
- Cited by
- 225
- References
- 148
- Citations by year
- 2026: 31 · 2025: 32 · 2024: 49 · 2023: 40 · 2022: 42 · 2021: 23 · 2020: 8
- FWCI
- 2.70
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Hepatology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion, other-oa)
- Funders
- Fondation pour la Recherche Médicale
- Fundação para a Ciência e a Tecnologia
- National Institutes of Health
- H2020 Marie Skłodowska-Curie Actions
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- lytic cell death, metabolic liver disease, pyroptosis, ferroptosis, apoptosis, liver inflammation, liver fibrosis, liver cirrhosis, hepatic stellate cells, non-alcoholic fatty liver disease, alcoholic liver disease, therapeutic target
- MeSH terms
- Pyroptosis, Necroptosis, Ferroptosis, Regulated Cell Death, Humans, Liver Diseases, Drug Discovery
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