ZNF143 suppresses mitophagy to drive MASLD progression by regulating SMURF1/TRPV1 axis.

Metabolically dysfunction-associated steatotic liver disease (MASLD), a globally prevalent metabolic condition, is increasingly linked to impaired mitophagy. However, its regulatory mechanisms in MASLD are not fully elucidated. This study investigated the role of Zinc finger protein 143 (ZNF143) in regulating hepatocyte mitophagy during MASLD development and the mechanisms involved. We employed two complementary MASLD models: (1) C57BL/6J mice fed a high-fat diet (HFD) for 16 weeks and (2) Huh-7 cells exposed to free fatty acid (FFA). Pathological changes were detected by H&E Staining. Cellular lipid deposition and mitochondrial damage were assessed using Oil Red O, JC-1 staining and transmission electron microscope (TEM), respectively. The intermolecular interaction was identified by dual-luciferase reporter assay, ChIP, and Co-IP. ZNF143 was upregulated in MASLD models, and its knockdown mitigated lipid accumulation and liver injury by activating hepatocyte mitophagy. ZNF143 promoted SMAD-specific E3 ubiquitin-protein ligase 1 (SMURF1) transcription by binding to its promoter region. Moreover, SMURF1 mediated transient receptor potential vanilloid type 1 (TRPV1) ubiquitination and degradation. Finally, knockdown of TRPV1 or overexpression of SMURF1 reversed the promoting effect of ZNF143 knockdown on mitophagy in FFA-treated Huh-7 cells. In short, ZNF143 upregulation exacerbated MASLD progression by mediating TRPV1 ubiquitination and degradation through transcriptionally activating SMURF1.