CD47-SIRPα axis blockade in NASH promotes necroptotic hepatocyte clearance by liver macrophages and decreases hepatic fibrosis
Open accessAbstract
Necroptosis contributes to hepatocyte death in nonalcoholic steatohepatitis (NASH), but the fate and roles of necroptotic hepatocytes (necHCs) in NASH remain unknown. We show here that the accumulation of necHCs in human and mouse NASH liver is associated with an up-regulation of the “don’t-eat-me” ligand CD47 on necHCs, but not on apoptotic hepatocytes, and an increase in the CD47 receptor SIRPα on liver macrophages, consistent with impaired macrophage-mediated clearance of necHCs. In vitro, necHC clearance by primary liver macrophages was enhanced by treatment with either anti-CD47 or anti-SIRPα. In a proof-of-concept mouse model of inducible hepatocyte necroptosis, anti-CD47 antibody treatment increased necHC uptake by liver macrophages and inhibited markers of hepatic stellate cell (HSC) activation, which is responsible for liver fibrogenesis. Treatment of two mouse models of diet-induced NASH with anti-CD47, anti-SIRPα, or AAV8-H1-shCD47 to silence CD47 in hepatocytes increased the uptake of necHC by liver macrophages and decreased markers of HSC activation and liver fibrosis. Anti-SIRPα treatment avoided the adverse effect of anemia found in anti-CD47–treated mice. These findings provide evidence that impaired clearance of necHCs by liver macrophages due to CD47-SIRPα up-regulation contributes to fibrotic NASH, and suggest therapeutic blockade of the CD47-SIRPα axis as a strategy to decrease the accumulation of necHCs in NASH liver and dampen the progression of hepatic fibrosis.
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Clearance of necroptotic hepatocytes is impaired in MASH and contributes to MASH progression.
“In a previous study, we showed that the clearance of necroptotic hepatocytes is impaired in MASH, contributing to MASH progression (15)”
From Impaired TIM4-mediated efferocytosis by liver macrophages contributes to fibrosis in metabolic dysfunction–associated steatohepatitis (2025) · cites this paper as [15]
The Introduction says the authors hypothesized that failed clearance of necroptotic hepatocytes might promote NASH progression and that their findings support this hypothesis. The Discussion reports that promoting clearance in experimental NASH was associated with less fibrosis, but says it remains unclear how much of the improvement was due to clearance itself. The citing sentence presents that contribution as established more firmly than the paper does. (LLM, conf=0.85)
Experimental — accuracy not yet measuredBlocking either SIRPα or CD47 improved necroptotic hepatocyte uptake and dampened progression to liver fibrosis, but these manipulations did not lower apoptotic hepatocytes.
“Although blocking either SIRPα or CD47 improved necroptotic hepatocyte uptake and dampened the progression to liver fibrosis, these manipulations did not lower apoptotic hepatocytes (15).”
From Impaired TIM4-mediated efferocytosis by liver macrophages contributes to fibrosis in metabolic dysfunction–associated steatohepatitis (2025) · cites this paper as [15]
The Results and Discussion report that blocking either CD47 or SIRPα increased necroptotic hepatocyte uptake and reduced fibrosis in mouse NASH models. The Results also say anti-CD47 did not increase clearance of apoptotic hepatocytes, but that is not the same as showing that apoptotic hepatocyte numbers did not fall; the cited passages do not establish that outcome for either blockade. Page numbers are unavailable in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredClearance of necroptotic hepatocytes is also defective in steatohepatitis/MASH, but its mechanism involves increases in SIRPα on MASH liver macrophages and CD47 on necroptotic hepatocytes rather than a decrease in a specific macrophage receptor.
“We showed that the clearance of necroptotic hepatocytes is also defective in steatohepatitis/MASH, but the mechanism is due to increases in signal regulatory protein alpha (SIRPα) on MASH liver macrophages and CD47 on necroptotic hepatocytes rather than a decrease in a specific macrophage receptor (15).”
From Impaired TIM4-mediated efferocytosis by liver macrophages contributes to fibrosis in metabolic dysfunction–associated steatohepatitis (2025) · cites this paper as [15]
The MASH fibrosis-protective mechanisms of boosting apoptotic hepatocyte clearance and necroptotic hepatocyte clearance are distinct and complementary, suggesting a possible additive benefit of enhancing both processes.
“the MASH fibrosis–protective mechanisms of boosting apoptotic hepatocyte clearance (here) and necroptotic hepatocyte clearance (15) are distinct and complementary, suggesting a possible additive benefit of enhancing both processes by combination cell or RNA therapy.”
From Impaired TIM4-mediated efferocytosis by liver macrophages contributes to fibrosis in metabolic dysfunction–associated steatohepatitis (2025) · cites this paper as [15]
Efferocytosis of hepatocyte-derived debris by SIRPα+ liver macrophages (both KC-derived and monocyte-derived) represses the onset of liver fibrosis.
“Interestingly, efferocytosis of hepatocyte-derived debris by SIRPα+ liver macrophages (both KC-derived and monocyte-derived) represses the onset of liver fibrosis [80, 81].”
From Inflammation and immunity in liver homeostasis and disease: a nexus of hepatocytes, nonparenchymal cells and immune cells (2025) · cites this paper as [80]
The upregulation of "don't-eat-me" signals via CD47 on hepatocytes and its receptor anti-SIRPa on macrophages can lead to a similar suppression of efferocytosis and increased fibrosis in MASLD.
“The upregulation of “don’t-eat-me” signals” via CD47 on hepatocytes and its receptor anti-SIRPa on macrophages can lead to a similar suppression of efferocytosis and increased fibrosis in MASLD [80].”
From Inflammation and immunity in liver homeostasis and disease: a nexus of hepatocytes, nonparenchymal cells and immune cells (2025) · cites this paper as [80]
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Huang, H., Fan, S., Zhou, X., Liu, Y., Xiao, L., Liao, L., Huang, J. L., Shi, C., Liang, Y., Fu, R., et al. (2021) · Acta Pharmacologica Sinica · doi:10.1038/s41401-021-00725-1 · Cited by 26 · see citing works
Tao, H.-C., Chen, K., Wang, X., Chen, B., Zhao, W., Zheng, Y., & Yang, Y. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00148 · Cited by 24 · see citing works
Self-citationThe molecular basis for current targets of NASH therapies
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Hasui, N., Sakaguchi, K., Ogawa, T., Sakamoto, Y., & Shimizu, T. (2022) · Scientific Reports · doi:10.1038/s41598-022-09428-x · Cited by 9 · see citing works
Generation and Use of Chimeric RIP Kinase Molecules to Study Necroptosis
Rodríguez, D. A., & Green, D. R. (2018) · Methods in molecular biology · doi:10.1007/978-1-4939-8754-2_7 · Cited by 4 · see citing works
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Chimeric antigen receptor-modified macrophages ameliorate liver fibrosis in preclinical models
Dai, H., Zhu, C., Huai, Q., Xu, W., Zhu, J., Zhang, X., Zhang, X., Sun, B., Xu, H., Zheng, M., et al. (2024) · Journal of Hepatology · doi:10.1016/j.jhep.2024.01.034 · Cited by 114 · see citing works
Immunopathogenic mechanisms and immunoregulatory therapies in MASLD
He, Y., Chen, Y., Qian, S., van Der Merwe, S., Dhar, D., Brenner, D. A., & Tacke, F. (2025) · Cellular & Molecular Immunology · doi:10.1038/s41423-025-01307-5 · Cited by 81 · see citing works
Inflammation in Alcohol-Associated Hepatitis: Pathogenesis and Therapeutic Targets
Feng, D., Hwang, S., Guillot, A., Wang, Y., Guan, Y., Chen, C., Maccioni, L., & Gao, B. (2024) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2024.04.009 · Cited by 44 · see citing works
Efferocytosis 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
Self-citationShi, H., Wang, X., Sloas, C., Gerlach, B., Yurdagul, A., Moore, M. P., Jung, E. J., Mirshahi, F., Ronzoni, L., Sanyal, A. J., et al. (2025) · Science Translational Medicine · doi:10.1126/scitranslmed.adv2106 · Cited by 30 · see citing works
Self-citationMacrophage heterogeneity in liver fibrosis
Wang, W., Li, S., Liu, Y., Ding, X., Yang, Y., Chen, S., Cao, J., Tacke, F., Dong, W., & Lan, T. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1639455 · Cited by 8 · see citing works
- Authors
- Shi, H., Wang, X., Li, F., Gerlach, B. D., Yurdagul, A., Moore, M. P., Zeldin, S., Zhang, H., Cai, B., Zheng, Z., Valenti, L., & Tabas, I.
- Affiliations
- Columbia University Irving Medical Center (US)
- University of Milan (IT)
- Corresponding author
- Shi, Hongxue
- Tabas, Ira
- ORCID
- Venue
- Science Translational Medicine
- Published
- 2022-11-23
- Volume
- 14
- Issue
- 672
- Pages
- eabp8309-eabp8309
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- PMC
- PMC10199725
- OpenAlex
- W4309821902
- Cited by
- 85
- References
- 74
- Citations by year
- 2026: 16 · 2025: 33 · 2024: 19 · 2023: 17
- FWCI
- 6.59
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science Translational Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Heart Association (20POST35130003, P30CA013696, 19CDA34660043)
- American Liver Foundation
- Pharmaceutical Research and Manufacturers of America Foundation
- University of Minnesota (HHSN276201200017C)
- University of Pittsburgh
- Monique Weill-Caulier Trust
- European Federation of Pharmaceutical Industries and Associations (777377)
- European Commission (777377, 101016726, RF-2016-02364358, HORIZON2020)
- Ministero della Salute (101016726, RF- 2016-02364358, 777377)
- National Institutes of Health (HHSN276201200017C, T32 5T32HL007343-42, CA013696, UL1TR001873)
- National Heart, Lung, and Blood Institute (R00HL130574, R00HL145131, R01HL151611, T32HL007343)
- National Cancer Institute (CA013696, P30CA013696)
- National Institute of General Medical Sciences (R35GM147269)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK116620, R00DK115778, R01DK133694, P30DK132710)
- U.S. National Library of Medicine (HHSN276201200017C)
- National Center for Research Resources (S10RR025686)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- CD47, SIRPα, nonalcoholic steatohepatitis, necroptosis, hepatocyte clearance, hepatic macrophages, liver fibrosis, hepatic stellate cell activation, don't eat me signal, anti-CD47 antibody, anemia, diet-induced NASH
- MeSH terms
- Animals, Humans, Liver Cirrhosis, Macrophages, Mice, Inbred C57BL, Hepatocytes, Mice, CD47 Antigen, Non-alcoholic Fatty Liver Disease
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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