Enhanced nuclear localization of small heterodimer partner in metabolic dysfunction-associated steatohepatitis

Background & Aims: The nuclear factor small heterodimer partner (SHP) plays a dual function in maintaining bile acid (BA) homeostasis and exerting anti-inflammatory effects. While SHP might be associated with metabolic dysfunction-associated steatohepatitis (MASH), its role in patients remains unclear. Methods: Liver tissue and serum samples were collected from 69 patients with MASH and 10 healthy controls. The subcellular distribution of SHP and related proteins in liver tissue were analyzed to correlate with MASH-associated pathological characteristics. In vitro studies were conducted to elucidate the underlying mechanisms and clinical relevance of SHP nuclear translocation in MASH. Results: Compared with controls, patients with MASH demonstrated a higher nuclear SHP ratio (51.7% vs. 1.55%, p <0.001), which correlated with the severity of hepatitis and steatosis, but not with serum BA levels. The nuclear SHP ratio increased in parallel with atypical protein kinase C zeta (PKCζ) signal intensity and showed high co-localization with nucleoporin RanBP2. In vitro experiments demonstrated that both toxic fatty acid and inflammatory cytokine could induce SHP nuclear translocation, which was blocked by PKCζ inhibition. SHP knockdown increased basal innate immune activity, accelerated intracellular lipid accumulation, and recapitulated a MASH-like gene profile that facilitates BA accumulation. Conclusions: Nuclear SHP accumulation is a distinctive feature of MASH pathology. This PKCζ-dependent process may exert anti-inflammation and anti-cholestasis function in patients with MASH. Impact and implications: The nuclear factor small heterodimer partner (SHP) plays a dual role in maintaining bile acid homeostasis and suppressing inflammation. In patients with metabolic dysfunction-associated steatohepatitis (MASH), we identified a pathological increase in the hepatocellular nuclear SHP ratio, likely triggered by lipid overload and inflammatory stimuli, and dependent on PKCζ activation. SHP knockdown in vitro induced cellular steatosis, innate immune responses, and leading to a cholestatic gene expression profile. These findings highlight SHP as a potential therapeutic target in MASH.