USP25 directly interacts with and deubiquitinates PPARα to increase PPARα stability in hepatocytes and attenuate high-fat diet-induced MASLD in mice.
Summary
This mechanistic study reveals a USP25–PPARα pathway in hepatocytes: USP25 directly deubiquitinates PPARα (removing K48 chains at Lys429 via His608), stabilizing it and reducing lipid accumulation. USP25 expression is reduced in human and mouse MASLD; genetic loss worsens HFD-induced steatosis, while hepatocyte USP25 induction is protective, effects that require PPARα.
Key Findings
- Hepatic USP25 expression is reduced in human and mouse MASLD.
- Usp25 deficiency exacerbates HFD-induced steatosis; hepatocyte USP25 induction protects against MASLD.
- USP25 directly binds PPARα and removes K48 ubiquitin chains at Lys429 via His608, stabilizing PPARα; protection is lost in Ppara-deficient mice.
Clinical Implications
While preclinical, targeting USP25 or its interaction with PPARα could enhance fatty acid oxidation and reduce steatosis in MASLD. Biomarker development (hepatic USP25 expression) may stratify patients for future therapies.
Why It Matters
Identifies a druggable deubiquitinase–nuclear receptor axis with clear in vivo validation, opening a new therapeutic avenue for MASLD beyond traditional metabolic targets.
Limitations
- Preclinical models; absence of interventional human data
- Potential off-target effects of USP25 modulation not fully characterized
Future Directions
Develop small-molecule USP25 modulators; validate hepatic USP25 levels as biomarkers; test translational efficacy in human organoids and early-phase MASLD trials.
Study Information
- Study Type
- Basic/Mechanistic Research
- Research Domain
- Pathophysiology
- Evidence Level
- V - Preclinical mechanistic study in cells and mice
- Study Design
- OTHER