Nrf2 promotes MASLD-HCC progression via SHP-mediated hepatic lipogenesis activation

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading risk factor for hepatocellular carcinoma (HCC), yet the molecular mechanisms driving this progression remain incompletely defined. The nuclear factor erythroid-2 related factor 2 (Nrf2), a master regulator of antioxidant signaling, has been implicated in hepatic lipid metabolism, but its role in MASLD-HCC pathogenesis is controversial. We analyzed Nrf2 expression in human fatty liver tissues from MASLD patients ( n = 12) and non-fatty controls ( n = 9) using immunohistochemistry and immunofluorescence. Functional studies employed hepatocyte-specific Nrf2 knockout and overexpression mice, along with HCC cell lines (Bel7402, Huh7) subjected to Nrf2 modulation. Lipid accumulation, gene expression, promoter activity, and inflammatory markers were assessed through biochemical assays, qRT-PCR, Western blotting, luciferase reporter assays, and ELISA. Nrf2 expression was significantly elevated in fatty livers, with further upregulation in MASLD-HCC tissues. Enforced Nrf2 expression promoted lipid deposition in HCC cells, while Nrf2 knockdown reduced triglyceride accumulation and lipid droplet formation. Mechanistically, Nrf2 increased SHP promoter reporter activity via antioxidant response elements(AREs), as confirmed by luciferase assays, suggesting that SHP is a transcriptional target of Nrf2. SHP knockdown abolished Nrf2-induced lipogenesis and attenuated MASLD progression in vivo. In a MASLD-HCC mouse model, Nrf2 overexpression exacerbated steatosis, inflammation, and tumorigenesis, effects reversed by SHP inhibition. These findings suggest that Nrf2 promotes hepatic lipogenesis, at least in part via SHP-mediated mechanisms, thereby accelerating MASLD progression to HCC. The Nrf2-SHP axis represents a critical pathway in MASLD-HCC pathogenesis and a promising therapeutic target for disease intervention.