Computational-experimental integration reveals PPARγ/Nrf2-GPX4 dual-targeting by combined selenomethionine-magnolol as a novel therapy for sarcopenic obesity.

Sarcopenic obesity (SO), characterized by concurrent muscle loss and excessive adiposity, lacks effective interventions. This study investigated the enhanced effects of the selenomethionine (Se-Met) and magnolol (Mag) combination against SO using an integrated computational-experimental approach. Network pharmacology and molecular docking predicted peroxisome proliferator-activated receptor γ (PPARγ) and the nuclear factor erythroid 2-related factor 2 - glutathione peroxidase 4 (Nrf2 - GPX4) axis as core targets, which was corroborated by single-cell transcriptomic data analysis showing their co-expression in muscle progenitor cells. In high-fat diet ‌(HFD)-fed mice, the combined Se-Met and Mag treatment ameliorated metabolic dysregulation, reduced intramuscular lipid deposition, and improved muscle function more effectively than monotherapies. In C2C12 myotubes, the combination co-activated PPARγ to enhance lipid clearance and potentiated the Nrf2-GPX4 antioxidant axis. Notably, it modulated ferroptosis-related signaling by downregulating acyl-CoA synthetase long-chain family member 4 (ACSL4) and upregulating ferritin heavy chain 1 (FTH1) and heme oxygenase-1 (HO-1), an effect abolished by Nrf2 inhibition. Pharmacological inhibition of either PPARγ or Nrf2 reversed the protective benefits. Our findings reveal that Se-Met and Mag in combination target PPARγ and Nrf2-GPX4 pathways while regulating ferroptosis-related signaling to alleviate ferroptosis-associated markers, with phenotypic characteristics consistent with ferroptosis inhibition, thereby offering a novel nutraceutical strategy for SO.