An integrated view of anti-inflammatory and antifibrotic targets for the treatment of NASH

In the paper

“Wound healing in the liver is dynamic and reversible,105 with ample evidence of fibrosis regression after effective treatment of viral hepatitis, and even following bariatric surgery in patients with NASH.106”

What the sources say

• Not checked yetcites [105] Kisseleva, 2021, Molecular and cellular mechanisms of liver fibrosis and its regression, Nat Rev Gastroenterol Hepatol source
• Supported

  The Discussion reports that fibrosis regressed in 70% of patients after long-term resolution of NASH following bariatric surgery. It also describes gradual improvement over five years. The citation supports the bariatric-surgery portion of the sentence; the viral-hepatitis statement is not the part attributed to this source. (LLM, conf=0.94)

  cites [106] Lassailly, 2020, Bariatric surgery provides long-term resolution of nonalcoholic steatohepatitis and regression of fibrosis, Gastroenterology source

In the paper

“While belapectin’s safety and tolerability were good, belapectin did not improve clinically relevant endpoints including fibrosis regression.”

What the sources say

• Supported

  The paper’s phase 2b study of 162 patients found belapectin safe and well tolerated, with no significant overall reduction in HVPG or fibrosis versus placebo (Conclusions). The Discussion likewise reports no significant changes in liver histology or cirrhosis complications, while noting a benefit in a subgroup without baseline varices. (LLM, conf=0.92)

  cites [103] Chalasani, 2020, Effects of belapectin, an inhibitor of galectin-3, in patients with nonalcoholic steatohepatitis with cirrhosis and portal hypertension, Gastroenterology source

In the paper

“lipotoxicity – defined as the generation of injurious lipid metabolites – is a key feature of progressive NAFLD, involving production of reactive oxygen species, mitochondrial dysfunction and the development of endoplasmic reticulum stress.3”

What the sources say

• Not checked yetcites [3] Loomba, 2021, Mechanisms and disease consequences of nonalcoholic fatty liver disease, Cell source

In the paper

“The natural course of NAFLD is heterogeneous, with substantial inter-patient variability, which is influenced by several non-modifiable (age, sex, race/ethnicity, family history, genetics) and modifiable (lifestyle/diet/exercise, comorbidities, drugs, alcohol) risk factors.2,3”

What the sources say

• Not checked yetcites [2] Powell, 2021, Non-alcoholic fatty liver disease, Lancet source
• Not checked yetcites [3] Loomba, 2021, Mechanisms and disease consequences of nonalcoholic fatty liver disease, Cell source

In the paper

“Because fibrosis is the most compelling predictor of outcomes, current and future therapies must improve fibrosis”

In the paper

“Structurally engineered fatty acids, such as icosabutate, improve resistance to peroxidative processes, and thus represent a promising approach to maintaining the beneficial metabolic effects of long-chain omega-3 fatty acids.15”

What the sources say

• Not checked yetcites [15] Fraser, 2022, A structurally engineered fatty acid, icosabutate, suppresses liver inflammation and fibrosis in NASH, J Hepatol source

In the paper

“Long-chain omega-3 fatty acids are known to beneficially regulate inflammatory pathways in the course of NASH, but therapeutic efficacy is highly limited by peroxidation and subsequent degradation.”

What the sources say

• Not checked yetcites [15] Fraser, 2022, A structurally engineered fatty acid, icosabutate, suppresses liver inflammation and fibrosis in NASH, J Hepatol source

In the paper

“For instance, bile acids are soluble mediators and key components of the gut-liver axis, connecting altered intestinal homeostasis (e.g. dysbiosis, increased permeability) to metabolic injury in NAFLD.35”

What the sources say

• Not checked yetcites [35] Tilg, 2022, Gut-liver axis: pathophysiological concepts and clinical implications, Cel Metab source

In the paper

“Ample preclinical evidence supports microbiota interventions to reduce NAFLD-related liver inflammation; however, evidence for long-term anti-inflammatory or antifibrotic effects in clinical trials is lacking.43”

What the sources say

• Not checked yetcites [43] Albillos, 2020, The gut-liver axis in liver disease: pathophysiological basis for therapy, J Hepatol source

In the paper

“Conceptually, reversing gut dysbiosis in NAFLD using pre-/pro-/antibiotics or faecal microbiota transplantation would reduce these inflammatory signals, reverse perturbations in gut barrier function (thereby further reducing endotoxin in the portal vein) and promote the endogenous production of beneficial mediators (FGFs, GLP-1, secondary bile acids).”

In the paper

“Liver macrophages are key to the pathogenesis of NAFLD (Fig. 2), as they accumulate with disease progression in human biopsies.50–52”

What the sources say

• Not checked yetcites [50] Guillot, 2023, Mapping the hepatic immune landscape identifies monocytic macrophages as key drivers of steatohepatitis and cholangiopathy progression, Hepatology source
• Not checked yetcites [51] Kazankov, 2019, The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, Nat Rev Gastroenterol Hepatol source
• Not checked yetcites [52] Wen, 2021, Hepatic macrophages in liver homeostasis and diseases-diversity, plasticity and therapeutic opportunities, Cell Mol Immunol source

In the paper

“When Kupffer cells sense hepatocyte stress and injury signals from other cells (or extrahepatic sources), they activate inflammatory signals, recruit monocytes (and other inflammatory cells) via chemokines and engulf cellular debris.53,54”

What the sources say

• Not checked yetcites [53] Marra, 2014, Roles for chemokines in liver disease, Gastroenterology source
• Not checked yetcites [54] Krenkel, 2017, Liver macrophages in tissue homeostasis and disease, Nat Rev Immunol source

In the paper

“For instance, activation of TLR4 via LPS leads to the release of pro-inflammatory cytokines (e.g., TNF, interleukin [IL]-6), but similar effects are also observed if free fatty acids bind to TLR4.63”

What the sources say

• Not checked yetcites [63] Shi, 2006, TLR4 links innate immunity and fatty acid-induced insulin resistance, J Clin Invest source

In the paper

“Kupffer cells comprise subsets/differentiation states, of which the CD206hi ESAM+ subtype (in mice) participates in fatty acid metabolism and may thereby directly drive NASH.56”

What the sources say

• Not checked yetcites [56] Bleriot, 2021, A subset of Kupffer cells regulates metabolism through the expression of CD36, Immunity source

In the paper

“Still, it is likely that immune subsets are more complex and nuanced than we currently understand in their functions during NASH.”

In the paper

“Given the opposing distribution of NKT cells and MAIT cells between human and mouse livers, findings about NKT cells from rodent models need to be interpreted with caution, and, from a functional perspective, MAIT cells may be the human counterpart of NKT cells.39,98”

What the sources say

• Not checked yetcites [39] Heymann, 2016, Immunology in the liver--from homeostasis to disease, Nat Rev Gastroenterol Hepatol source
• Not checked yetcites [98] Toubal, 2019, Mucosal-associated invariant T cells and disease, Nat Rev Immunol source

In the paper

“In NASH, XCR1 (X–C motif chemokine receptor 1)-expressing cDC1s are found abundantly in both patients with NASH and murine steatohepatitis, and correlate with NASH severity.85”

What the sources say

• Not checked yetcites [85] Deczkowska, 2021, XCR1(+) type 1 conventional dendritic cells drive liver pathology in non-alcoholic steatohepatitis, Nat Med source

In the paper

“While many of these discoveries have been based on mouse models, scRNA-seq analyses from human livers have also identified SAMs as a unique population located in the fibrotic niche of cirrhotic livers of different disease aetiologies.74”

What the sources say

• Not checked yetcites [74] Ramachandran, 2019, Resolving the fibrotic niche of human liver cirrhosis at single-cell level, Nature source

In the paper

“However, similar to the concern about using classical immunosuppressant drugs as highlighted above, their use in NAFLD is currently constrained by the lack of clinical data indicating beneficial effects on NASH and/or fibrosis, as well as their unfavourable safety profiles.79”

What the sources say

• Not checked yetcites [79] Wiering, 2023, Treating inflammation to combat non-alcoholic fatty liver disease, J Endocrinol

In the paper

“For instance, platelets bind to hepatic macrophages, and their activation further aggravates inflammation.80”

What the sources say

• Not checked yetcites [80] Malehmir, 2019, Platelet GPIbalpha is a mediator and potential interventional target for NASH and subsequent liver cancer, Nat Med source

In the paper

“These infiltrating monocyte-derived macrophages can promote both fibrogenesis71 and fibrosis resolution.72,73”

What the sources say

• Not checked yetcites [71] Krenkel, 2018, Therapeutic inhibition of inflammatory monocyte recruitment reduces steatohepatitis and liver fibrosis, Hepatology source
• Not checked yetcites [72] Pellicoro, 2014, Liver fibrosis and repair: immune regulation of wound healing in a solid organ, Nat Rev Immunol source
• Not checked yetcites [73] Baeck, 2014, Pharmacological inhibition of the chemokine C-C motif chemokine ligand 2 (monocyte chemoattractant protein 1) accelerates liver fibrosis regression by suppressing Ly-6C(+) macrophage infiltration in mice, Hepatology source

In the paper

“C–C motif chemokine receptor (CCR)2+ monocytes are important drivers of liver inflammation in NASH, and their therapeutic inhibition reduces NASH and fibrosis in rodent models.71,76”

What the sources say

• Not checked yetcites [71] Krenkel, 2018, Therapeutic inhibition of inflammatory monocyte recruitment reduces steatohepatitis and liver fibrosis, Hepatology source
• Not checked yetcites [76] Krenkel, 2017, Macrophages in nonalcoholic fatty liver disease: a role model of pathogenic immunometabolism, Semin Liver Dis source

In the paper

“More recently, a population of CXCR6+ Granzyme+ PD1+ CD8+ T cells was identified in NASH livers, which are directly activated by metabolic stimuli (including acetate and extracellular ATP) and collectively triggered auto-aggression against hepatocytes, in an antigen-independent fashion.87”

What the sources say

• Not checked yetcites [87] Dudek, 2021, Auto-aggressive CXCR6(+) CD8 T cells cause liver immune pathology in NASH, Nature source

In the paper

“Because inhibiting inflammatory signalling in macrophages is therapeutically challenging in NASH, augmenting anti-inflammatory signalling via targets that promote disease resolution may be the more realistic approach.”

In the paper

“Long-term risk of infection, specific side effects such as weight gain, and the lack of antigen-specific autoimmunity in NASH all argue against their use in the disease.”

In the paper

“In NAFLD and NASH, the NLR family pyrin domain containing 3 (NLRP3) inflammasome has been identified as a central driver of inflammation – via activation of caspase 1 and the release of inflammatory cytokines (e.g., IL-1β) – and as an inducer of inflammatory (“pyroptotic”) cell death.64”

What the sources say

• Not checked yetcites [64] Knorr, 2020, The NLRP3 inflammasome in alcoholic and nonalcoholic steatohepatitis, Semin Liver Dis source

In the paper

“These innate and unconventional immune cell populations are affected by interventions on the gut-liver axis and could represent promising targets for future NASH therapies as well.”

In the paper

“NKT cells are much more abundant in mouse livers than in humans, and they promote NASH, fibrosis and carcinogenesis in experimental models.86,96,97”

What the sources say

• Not checked yetcites [86] Wolf, 2014, Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes, Cancer Cell source
• Not checked yetcites [96] Syn, 2012, NKT-associated hedgehog and osteopontin drive fibrogenesis in non-alcoholic fatty liver disease, Gut source
• Not checked yetcites [97] Wehr, 2013, Chemokine receptor CXCR6-dependent hepatic NK T Cell accumulation promotes inflammation and liver fibrosis, J Immunol source

In the paper

“However, despite favourable tolerability as well as antifibrotic efficacy after 1 year of treatment in adults with NASH and liver fibrosis in a phase II trial,78 cenicriviroc did not demonstrate sustained antifibrotic efficacy after 1 year of treatment in a larger phase III clinical trial following interim analysis, leading to the termination of its development as a monotherapy in NASH.79”

What the sources say

• Not checked yetcites [78] Ratziu, 2020, Cenicriviroc treatment for adults with nonalcoholic steatohepatitis and fibrosis: final analysis of the phase 2b CENTAUR study, Hepatology source
• Not checked yetcites [79] Wiering, 2023, Treating inflammation to combat non-alcoholic fatty liver disease, J Endocrinol

In the paper

“For instance, NK cells are considered anti-fibrogenic due to their capacity to eliminate HSCs,91 but they may also support hepatic inflammation and alter metabolism.92”

What the sources say

• Not checked yetcites [91] Gur, 2012, NKp46-mediated killing of human and mouse hepatic stellate cells attenuates liver fibrosis, Gut source
• Not checked yetcites [92] Martinez-Chantar, 2021, Revisiting the role of natural killer cells in non-alcoholic fatty liver disease, Front Immunol source

In the paper

“Of note, ILC1, ILC2 and ILC3 populations have been implicated in metabolic disorders beyond NAFLD (e.g. obesity).93,94”

What the sources say

• Not checked yetcites [93] O'Sullivan, 2016, Adipose-resident group 1 innate lymphoid cells promote obesity-associated insulin resistance, Immunity source
• Not checked yetcites [94] Brestoff, 2015, Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity, Nature source

In the paper

“Based on proteo-genomic data combined with spatial information, LAMs (SAMs) locate near intrahepatic bile ducts in homeostasis, but shift towards steatotic areas, fostered by increased C–C motif chemokine ligand 2 (CCL2) expression by HSCs.75”

What the sources say

• Not checked yetcites [75] Guilliams, 2022, Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches, Cell source

In the paper

“Neutrophils are also abundant in NASH livers, particularly in early stages, and may contribute to inflammation by releasing toxic molecules including proteases, oxidants, cytokines and NETs (neutrophil extracellular traps).81”

What the sources say

• Not checked yetcites [81] Jorch, 2017, An emerging role for neutrophil extracellular traps in noninfectious disease, Nat Med source

In the paper

“In addition, quiescent and activated HSCs are transcriptomically distinct in human livers, with activated HSCs downregulating vitamin A storage-related genes and upregulating profibrogenic genes such as collagen I.113”

What the sources say

• Not checked yetcites [113] MacParland, 2018, Single cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations, Nat Commun source

In the paper

“HSC activation into myofibroblasts requires energy, so that HSC activation necessitates an intense metabolic reprogramming through activation of glycolysis, glutaminolysis (using glutamine as an additional source of ATP), and lipogenesis.70”

What the sources say

• Not checked yetcites [70] Gilgenkrantz, 2021, Targeting cell-intrinsic metabolism for antifibrotic therapy, J Hepatol source

In the paper

“Moreover, the evolution of a dense autocrine network indicates that as fibrosis advances, the repertoire of therapeutic targets evolves, so that treatments for early disease may be less effective in advanced fibrosis.”

In the paper

“Intracellular lipids released during autophagy act as an additional energy source for HSC activation, revealing another therapeutic vulnerability that could be targeted by antifibrotic strategies.122”

What the sources say

• Not checked yetcites [122] Hernandez-Gea, 2012, Autophagy releases lipid that promotes fibrogenesis by activated hepatic stellate cells in mice and in human tissues, Gastroenterology source

In the paper

“Most recently, the fatty acid synthase inhibitor denifanstat (TVB-2640) also demonstrated antifibrotic activity in HSCs while improving NASH.121”

What the sources say

• Not checked yetcites [121] O'Farrell, 2022, FASN inhibition targets multiple drivers of NASH by reducing steatosis, inflammation and fibrosis in preclinical models, Sci Rep

In the paper

“As noted above, autophagy (i.e. the lysosome-dependent orderly degradation and recycling of cellular components) may generate energy during HSC activation,127 such that inhibiting autophagy would be antifibrotic.”

What the sources say

• Not checked yetcites [127] Thoen, 2011, A role for autophagy during hepatic stellate cell activation, J Hepatol source

In the paper

“The acetyl-CoA carboxylase inhibitors firsocostat, as well as clesacostat (PF-05221304), both reduced liver fibrosis in animal models, independently of their anti-steatotic effects, and HSC activation in vitro.117,118”

What the sources say

• Not checked yetcites [117] Bates, 2020, Acetyl-CoA carboxylase inhibition disrupts metabolic reprogramming during hepatic stellate cell activation, J Hepatol source
• Not checked yetcites [118] Ross, 2020, Acetyl-CoA carboxylase inhibition improves multiple dimensions of NASH pathogenesis in model systems, Cell Mol Gastroenterol Hepatol source

In the paper

“Targeting TGF-β directly with antibodies (e.g., fresolimumab or metelimumab) has been largely terminated due to dose-limiting adverse events, since systemic inhibition of the cytokine is immunosuppressive and may promote cancer.114”

What the sources say

• Not checked yetcites [114] Henderson, 2020, Fibrosis: from mechanisms to medicines, Nature source

In the paper

“HSCs express several nuclear receptors that a retargets of investigational drugs for NASH, including low levels of FXR, high levels of LXR, robust levels of THR-α (but low levels of THR-β) and different isoforms of PPARs.129”

What the sources say

• Not checked yetcites [129] Konigshofer, 2021, Nuclear receptors in liver fibrosis, Biochim Biophys Acta Mol Basis Dis source

In the paper

“During HSC transdifferentiation to myofibroblasts in vitro, glucose transporters (e.g., glucose transporter 1) and glycolytic enzymes (e.g., hexokinase 2) are induced, and gluconeogenesis is downregulated.70”

What the sources say

• Not checked yetcites [70] Gilgenkrantz, 2021, Targeting cell-intrinsic metabolism for antifibrotic therapy, J Hepatol source

In the paper

“Thus, hexokinase inhibitors (e.g., PF-06835919) or SGLT2 (sodium glucose linked transporter 2) inhibitors like empaglifozin, licoglifozin or dapaglifozin may attenuate HSC activation and fibrogenesis.”

In the paper

“The selective inhibition of stearoyl-CoA desaturase 1 in HSCs reduced their activation and inhibited fibrosis in rodent models.120”

What the sources say

• Not checked yetcites [120] Lai, 2017, Stearoyl-CoA desaturase promotes liver fibrosis and tumor development in mice via a wnt positive-signaling loop by stabilization of low-density lipoprotein-receptor-related proteins 5 and 6, Gastroenterology source

In the paper

“Similar to cytokines, galectin 3 is secreted by macrophages upon liver injury in NASH and has profibrotic activity.102”

What the sources say

• Not checked yetcites [102] Al Attar, 2021, Review of galectin-3 inhibitors in the treatment of nonalcoholic steatohepatitis, Expert Rev Clin Pharmacol source

In the paper

“HSC activation in NASH is mainly driven by: i) soluble signals such as platelet-derived growth factor (PDGF), vascular endothelial growth factor, and transforming growth factor (TGF)-β; ii) by paracrine interactions with macrophages and other immune cells, as well as hepatocytes and endothelial cells; it is also accompanied by metabolic reprogramming.70,108”

What the sources say

• Not checked yetcites [70] Gilgenkrantz, 2021, Targeting cell-intrinsic metabolism for antifibrotic therapy, J Hepatol source
• Not checked yetcites [108] Tsuchida, 2017, Mechanisms of hepatic stellate cell activation, Nat Rev Gastroenterol Hepatol source

In the paper

“The disease-driving pathways of NASH converge in fibrosis (Fig. 3), an aberrant wound-healing process resulting not only in scarring (extracellular matrix deposition), but also in the loss of functional hepatocytes and chronic inflammation.104”

What the sources say

• Not checked yetcites [104] Schwabe, 2020, Mechanisms of fibrosis development in nonalcoholic steatohepatitis, Gastroenterology source

In the paper

“Nonetheless, one important lesson from alcohol-associated hepatitis is that the broad application of steroids, anakinra (recombinant IL-1 receptor antagonist), pentoxifyllin (which inhibits TNF synthesis) or infliximab (anti-TNF antibody) does not provide benefit, and may aggravate this inflammatory condition.101”

What the sources say

• Not checked yetcites [101] Bataller, 2022, Alcohol-associated hepatitis, N Engl J Med source

In the paper

“However, proper macrophage differentiation is probably required, because mouse models of fibrosis have demonstrated that the adoptive transfer of “non-programmed” immature bone marrow monocytes aggravates liver fibrosis, while the intravenous administration of properly (ex vivo) differentiated macrophages ameliorates hepatic fibrosis.149,150”

What the sources say

• Not checked yetcites [149] Thomas, 2011, Macrophage therapy for murine liver fibrosis recruits host effector cells improving fibrosis, regeneration, and function, Hepatology source
• Not checked yetcites [150] Ma, 2017, Cytotherapy with M1-polarized macrophages ameliorates liver fibrosis by modulating immune microenvironment in mice, J Hepatol source

In the paper

“Nonetheless, the clinical efficacy of this approach is unknown, and many questions remain unanswered, including the efficiency of engraftment, cell viability, phenotype stability, and whether macrophages are the optimal cell for this purpose.”

In the paper

“Since HSCs/myofibroblasts, matrix proteins and fibrolytic pathways are challenging therapeutic targets, cell-based therapies are being explored to augment anti-inflammatory and antifibrotic activity.”

In the paper

“While MSC transfer led to promising antifibrotic effects in mouse models, clinical trials on MSCs in humans have yielded mixed results.145”

What the sources say

• Not checked yetcites [145] Dwyer, 2021, Cell therapy for advanced liver diseases: repair or rebuild, J Hepatol source

In the paper

“In this proof-of-concept trial, apheresis-derived autologous CD14+ monocytes were differentiated ex vivo into a restorative phenotype (CD14+, high 25F9, CD206, CD163 and CD169). The single injection of different doses of these macrophages appeared safe and was associated with a (slight) reduction in the model of end-stage liver disease score.151”

What the sources say

• Not checked yetcites [151] Moroni, 2019, Safety profile of autologous macrophage therapy for liver cirrhosis, Nat Med source

In the paper

“Consistently, clinical data with obeticholic acid reported an improvement of liver fibrosis in non-cirrhotic NASH,132 but not in patients with compensated cirrhosis.”

What the sources say

• Not checked yetcites [132] Younossi, 2019, Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial, Lancet source

In the paper

“The mechanisms underlying disease regression are less well understood, but several molecular and cellular principles have been identified based on mouse models24 as well as samples from patients with NASH following disease regression, for example after bariatric surgery or lifestyle modifications.137”

What the sources say

• Not checked yetcites [24] Peiseler, 2022, Immune mechanisms linking metabolic injury to inflammation and fibrosis in fatty liver disease - novel insights into cellular communication circuits, J Hepatol source
• Not checked yetcites [137] Haas, 2019, Transcriptional network analysis implicates altered hepatic immune function in NASH development and resolution, Nat Metab source

In the paper

“Macrophages can adopt a repair phenotype that promotes fibrosis regression and proper tissue regeneration, supporting the concept of programmed macrophage transplantation as a therapeutic strategy (Fig. 2).”

In the paper

“Hepatic fibrosis is dynamic and reversible prior to the development of cirrhosis, and even cirrhosis may be reversible if not too advanced; however, specific features of advanced liver disease such as capillarisation of the liver sinusoids might be less reversible.105”

What the sources say

• Not checked yetcites [105] Kisseleva, 2021, Molecular and cellular mechanisms of liver fibrosis and its regression, Nat Rev Gastroenterol Hepatol source

In the paper

“However, despite the relevance of inflammation and fibrosis to NAFLD-related outcomes, no “pure” anti-inflammatory or antifibrotic compound has been approved for the treatment of NASH. This is likely related to the complexity of the processes driving inflammation and fibrosis, but also to redundancy in inflammatory and fibrogenic signalling.”

In the paper

“Currently, a retinoid-conjugated lipid nanoparticle containing small-interfering RNA against heat-shock protein 47 (HSP47, BMS-986263) is being tested in a phase II clinical trial for patients with compensated NASH cirrhosis, since it demonstrated favourable safety and some efficacy in patients regressing from hepatitis C virus-associated fibrosis.135”

What the sources say

• Not checked yetcites [135] Lawitz, 2022, BMS-986263 in patients with advanced hepatic fibrosis: 36-week results from a randomized, placebo-controlled phase 2 trial, Hepatology source

In the paper

“Since MSCs appear to exert many of their beneficial actions via the release of extracellular vesicles, the use of MSC-derived extracellular vesicles instead of cells could be an interesting cell-free, less immunogenic, and less toxic alternative antifibrotic strategy.155”

What the sources say

• Not checked yetcites [155] Psaraki, 2022, Extracellular vesicles derived from mesenchymal stem/stromal cells: the regenerative impact in liver diseases, Hepatology source

In the paper

“Nonetheless, the clinical translation of this approach is challenging because uPAR is not only expressed on senescent cells, but also on several immune cell populations including neutrophils and macrophages, and cellular senescence has cell type-dependent functions in fibrosis that may undermine efforts to deplete senescent cells as a therapy.”

In the paper

“On the other hand, other efforts to target fibrogenic cells in the heart by targeting cell surface FAP-1 (fibroblast activating protein) are very encouraging, and may be adaptable to liver disease.147,148”

What the sources say

• Not checked yetcites [147] Friedman, 2022, Fighting cardiac fibrosis with CAR T cells, N Engl J Med source
• Not checked yetcites [148] Rurik, 2022, CAR T cells produced in vivo to treat cardiac injury, Science source

In the paper

“Moreover, targeting critical downstream pathways of inflammation and fibrosis, for example by depleting immune cells or antagonising cytokines, carries a high risk of undermining important immune surveillance functions,158 making such approaches unacceptably risky for a chronic condition such as NASH.”

What the sources say

• Not checked yetcites [158] Jenne, 2013, Immune surveillance by the liver, Nat Immunol source

In the paper

“iii) deactivation or elimination of myofibroblasts by reverting them to a quiescent HSC-like phenotype, via HSC senescence or by elimination of activated HSCs via NK cells or T cells 91,105,141;”

What the sources say

• Not checked yetcites [91] Gur, 2012, NKp46-mediated killing of human and mouse hepatic stellate cells attenuates liver fibrosis, Gut source
• Not checked yetcites [105] Kisseleva, 2021, Molecular and cellular mechanisms of liver fibrosis and its regression, Nat Rev Gastroenterol Hepatol source
• Not checked yetcites [141] Koda, 2021, CD8(+) tissue-resident memory T cells promote liver fibrosis resolution by inducing apoptosis of hepatic stellate cells, Nat Commun source

In the paper

“Regardless, efficient cytotherapy will require long-term stability of a “repair macrophage” phenotype.”

In the paper

“However, HSC specificity is critical as some “HSC-specific nanoparticles” target macrophages, possibly through their phagocytic capacity.136”

What the sources say

• Not checked yetcites [136] Ergen, 2019, Liver fibrosis affects the targeting properties of drug delivery systems to macrophage subsets in vivo, Biomaterials source

In the paper

“This would, however, support the concept of combinatorial treatment for NASH, as combining anti-inflammatory strategies could amplify the efficacy of metabolic drugs and overcome signalling redundancies.156”

What the sources say

• Not checked yetcites [156] Ratziu, 2023, Rational combination therapy for NASH: insights from clinical trials and error, J Hepatol source

In the paper

“Full matrix degradation also requires reduced levels of MMP-inhibitory proteins (e.g. TIMP [tissue inhibitor of MMP]) and the presence of phagocytic macrophages.142”

What the sources say

• Not checked yetcites [142] Caligiuri, 2021, Cellular and molecular mechanisms underlying liver fibrosis regression, Cells