Phloretin Suppresses the mPTP Abnormal Opening via the SHP-2/JAK2/BAX Axis to Ameliorate Nonalcoholic Steatohepatitis

Mitochondrial dysfunction, particularly driven by aberrant mitochondrial permeability transition pore (mPTP) opening, is a key pathogenic mechanism in nonalcoholic steatohepatitis (NASH). This study demonstrates for the first time that phloretin (Pht), a natural apple-derived dihydrochalcone, effectively inhibits this pathology by targeting SHP-2. Pht modulates the SHP-2/JAK2/BAX signaling axis, significantly suppressing the pathological mPTP opening. This action preserves mitochondrial homeostasis, evidenced by restored mitochondrial membrane potential, improved ultrastructural integrity, and the prevention of mitochondrial DNA (mtDNA) leakage into the cytosol. By blocking mtDNA escape, Pht inhibits the cytosolic mtDNA-induced activation of the cGAS-STING pathway and its downstream inflammatory cascade. Consequently, Pht ameliorates hepatic lipid metabolic dysregulation and inflammation. These findings reveal a novel SHP-2/JAK2/BAX-mPTP-mtDNA-cGAS signaling cascade through which dietary Pht alleviates NASH-associated mitochondrial inflammation. This work provides a crucial mechanistic foundation and identifies potential targets for developing functional foods or interventions aimed at promoting mitochondrial homeostasis.