A Cell‐Penetrating Scorpion Venom Peptide Disrupts the HSP90β‐PPARα Interaction to Ameliorate Metabolic Dysfunction‐Associated Steatotic Liver Disease

ABSTRACT As a key regulator of hepatic lipid homeostasis and inflammation, PPARα represents an important therapeutic target for MASLD. However, clinical trials with PPARα agonists have demonstrated insufficient efficacy, notably failing to improve hepatic steatosis. Here, through a systematic screen, we identified BmK Tx‐2, a peptide from Buthus martensii Karsch (BmK) scorpion venom that has unique antisteatotic activity. BmK Tx‐2 effectively prevented diet‐induced MASL/MASH in mice by activating fatty acid β‐oxidation (FAO) in a PPARα‐dependent manner, as demonstrated by the abolished therapeutic effect on PPARα knockout mice. Mechanistically, we demonstrated that HSP90β acts as a suppressor of PPARα‐driven lipid metabolism in hepatocytes during MASLD progression. Liver‐specific HSP90β overexpression inhibited the PPARα‐mediated regulation of lipid metabolism and abolished the anti‐MASH effect of BmK Tx‐2. Structural analysis revealed that HSP90β interacts with PPARα through its K349, R405, K406, and D444 residues, thereby inhibiting PPARα nuclear translocation and transcriptional activity. Notably, BmK Tx‐2 efficiently internalized into hepatocytes and specifically bound to HSP90β via its V55 residue. This interaction disrupted the HSP90β–PPARα complex, promoted PPARα nuclear import, and subsequently activated PPARα‐mediated FAO. These findings establish the HSP90β–PPARα interaction as a promising therapeutic target for MASLD, with BmK Tx‐2 serving as a potential lead compound.