ArticleCell metabolism2025
Hepatic sphingomyelin phosphodiesterase 3 promotes steatohepatitis by disrupting membrane sphingolipid metabolism.
Article in Cell metabolism, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed.
- Longevity-driven hepatic transcriptional programs mediate resilience to diet-induced liver injury in Ames dwarf mice.GeroScience · 2026Article
- Neohesperidin Regulates Lipid Metabolism and Ameliorates MASLD by Targeting ECHS1.Phytotherapy research : PTR · 2026Article
- Causal Effects of Oral Microbiome, Circulating Metabolites, and Inflammatory Proteins on Recurrent Aphthous Stomatitis: A Two-Sample Mendelian Randomization Study.Oral health & preventive dentistry · 2026Article
- Sphingolipid Metabolism in Obesity: Bidirectional Regulation and Comparative Perspectives on Plant Sphingolipids.Nutrients · 2026Review
- Sphingolipid homeostasis and dysregulation in liver function and disease.Life metabolism · 2026Review
- MicroRNA-SIRT1 crosstalk in liver diseases: molecular regulation of metabolism, inflammation, and cell survival.Molecular biology reports · 2026Review
- Deep chemical structure graph learning deciphers the lipotoxicity code of hypertriglyceridemic pancreatitis.NPJ digital medicine · 2026Article
- Metabolic Pathways Linking Atherosclerotic Cardiovascular Disease With Metabolic Dysfunction-Associated Steatotic Liver Disease.Current atherosclerosis reports · 2026Review
- Mechanism of arbutin in metabolic dysfunction-associated fatty liver disease based on multi-omics research.Bioresources and bioprocessing · 2026Article
- An aging-related gene signature, featuring Cdkn2a, predicts prognosis and immunotherapy response in uterine corpus endometrial carcinoma.Discover oncology · 2026Article
- Metabolic reprogramming in cancer: dysregulation of glucose, lipid, and amino acid pathways and therapeutic opportunities.Molecular biomedicine · 2026Review
- Bidirectional Regulation between Metabolic Dysfunction-associated Steatotic Liver Disease and Sarcopenia via Liver-muscle Crosstalk.Journal of clinical and translational hepatology · 2026Article
- [Advances in research on metabolic associated fatty liver disease in 2025].Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology · 2026Review
- MLKL in liver parenchymal cells promotes liver cancer in murine metabolic dysfunction-associated steatotic liver disease.Cell death & disease · 2026Article
- Dysregulation of the AMPK-SREBP1-FASN axis in MASLD: driving a vicious cycle of lipotoxicity and metabolic-immune crosstalk.Lipids in health and disease · 2026Review
- Article
- Lipid metabolism drives podocyte injury in diabetic kidney disease.Frontiers in immunology · 2026Review
- Integrated multi-omics reveals acylcarnitine accumulation as an early driver of doxorubicin-induced cardiotoxicity targeted by chlorogenic acid.Frontiers in pharmacology · 2026Article
- Clinical insight-driven novel drug development: Multidisciplinary integration and transformative opportunities.Acta pharmaceutica Sinica. B · 2026Article
- Article
Corrections and comments
- Erratum issued
Authors and funding
21 authors.
Funding
Abstract
Metabolic-dysfunction-associated steatohepatitis (MASH) remains a major health challenge. Herein, we identify sphingomyelin phosphodiesterase 3 (SMPD3) as a key driver of hepatic ceramide accumulation through increasing sphingomyelin hydrolysis at the cell membrane. Hepatocyte-specific Smpd3 gene disruption or pharmacological inhibition of SMPD3 alleviates MASH, whereas reintroducing SMPD3 reverses the resolution of MASH. Although healthy livers express low-level SMPD3, lipotoxicity-induced DNA damage suppresses sirtuin 1 (SIRT1), triggering an upregulation of SMPD3 during MASH. This disrupts membrane sphingomyelin-ceramide balance and promotes disease progression by enhancing caveolae-dependent lipid uptake and extracellular vesicle secretion from steatotic hepatocytes to exacerbate inflammation and fibrosis. Consequently, SMPD3 acts as a central hub integrating key MASH hallmarks. Notably, we discovered a bifunctional agent that simultaneously activates SIRT1 and inhibits SMPD3, which shows significant therapeutic potential in MASH treatment. These findings suggest that inhibition of hepatic SMPD3 restores membrane sphingolipid metabolism and holds great promise for developing novel MASH therapies.
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