ArticleCell death and differentiation2025
USP25 directly interacts with and deubiquitinates PPARα to increase PPARα stability in hepatocytes and attenuate high-fat diet-induced MASLD in mice.
Article in Cell death and differentiation, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed.
- CircRPPH1 promotes hepatocellular carcinoma progression through inhibiting PPARα transcription and accelerating its ubiquitination and degradation.Cellular and molecular life sciences : CMLS · 2026Article
- The depletion of serine beta-lactamase-like protein (LACTB) ameliorates metabolic dysfunction-associated steatotic liver disease by reducing ubiquitin-mediated degradation of carnitine palmitoyltransferase 2.Diabetes, obesity & metabolism · 2026Article
- USP2 promotes metabolic dysfunction-associated steatotic liver disease progression via stabilization of PPARγ.Cell death and differentiation · 2026Article
- RNF128 regulates the adaptive metabolic response to fasting by modulating PPARα function.Cell death and differentiation · 2026Article
- Deubiquitinases in liver diseases: from mechanisms to targeted therapy.Science China. Life sciences · 2026Review
- USP25 inhibition ameliorates Parkinson's disease by restoring mitophagy.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Ubiquitin-specific protease 25: a new regulator for cardiovascular and cerebrovascular diseases.Frontiers in cell and developmental biology · 2026Review
- Ammonium Hydroxide Enhancement of Dietary Protein in High-Fat Diets Modulates Liver Metabolism Signaling in a Sex- and Age-Dependent Manner in C3H/HeJ Mice.International journal of molecular sciences · 2025Article
- MPPMolecular biology reports · 2025Article
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13 authors.
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Abstract
Recent studies have implicated altered ubiquitination/de-ubiquitination pathway in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we investigated the potential role of a deubiquitinase, ubiquitin-specific peptidase 25 (USP25), in MASLD. Analysis of mRNA profiling data showed that both human and mouse MASLD are associated with reduced expression of USP25 in hepatocytes. Usp25 deficiency exacerbated HFD-induced liver lipid accumulation and MASLD in mice. Rescue experiments with USP25 induction in hepatocytes protected mice against HFD-induced MASLD. Through comprehensive transcriptome sequence and pulldown-LC-MS/MS analysis, we identified that peroxisome proliferator-activated receptor α (PPARα) is involved in USP25's protective actions and may be the substrate protein of USP25. Cell-based experiments show that USP25 interacts with PPARα directly via its USP domain and the histidine at position 608 of USP25 exerts deubiquitination to increase protein stability by removing the K48 ubiquitin chain at PPARα's lysine at position 429. USP25 reduces palmitate (PA)-induced lipid accumulation in hepatocytes via increasing PPARα. Finally, we show that the protective effects of Usp25 induction are nullified in Ppara-deficient mice with HFD. In summary, this study presents a new USP25-PPARα axis in hepatocytes and highlights a novel function of USP25 in MASLD, suggesting that it may be targeted to combat the disease.
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