Steatosis paradox: Unraveling pathways of suppressive effect of hepatic steatosis on hepatitis B virus.

The global intersection of chronic hepatitis B (CHB) and metabolic dysfunction-associated steatotic liver disease (MASLD) has revealed an intriguing clinical paradox: hepatic steatosis is frequently associated with lower hepatitis B virus (HBV) viral loads, higher rates of HBsAg seroclearance, and even favorable clinical outcomes. Accumulating data suggest that lipid accumulation transforms hepatocytes into a hostile microenvironment for HBV through at least four pathways, including immune modulation, metabolic reprogramming, endoplasmic reticulum stress, and impaired autophagy. Deciphering these molecular pathways not only explains the unique natural history of CHB patients with concurrent MASLD but also highlights novel therapeutic targets such as selective modulators of cellular stress that could complement existing antivirals or immune enhancers to facilitate functional cure. In this review, the current evidence regarding the cellular mechanisms underlying the suppressive effect of steatosis on HBV is summarized, providing a translational roadmap for exploiting these virus-host metabolic interactions to develop next-generation, novel host-targeting therapies against HBV.