4-IPP Alleviates Dexamethasone-Induced Muscle Atrophy by Targeting the MIF/TXNIP/NLRP3 Axis

Sarcopenia, an age-related degenerative skeletal muscle disorder, is strongly associated with adverse clinical outcomes including recurrent falls, functional disability, frailty, and increased mortality. Emerging evidence suggests that systemic chronic inflammation plays a central role in muscle wasting. Although macrophage migration inhibitory factor (MIF) is a known pro-inflammatory cytokine in various inflammatory diseases, its role in sarcopenia development remains unclear. We found significantly elevated plasma levels of MIF, TNF-α, IL-6, and IL-8 in sarcopenia patients, which were inversely correlated with muscle strength. In vitro , we demonstrated that MIF exposure directly induced atrophy in C2C12 myotubes. Furthermore, our study showed that MIF induces excessive ROS production, activating the TXNIP/NLRP3 inflammasome pathway and subsequent pro-inflammatory responses. Consistent with these findings, in vivo administration of 4-IPP significantly alleviated muscle mass loss and functional decline in a Dexamethasone (DEX)-induced murine sarcopenia model. Our findings demonstrate that MIF is a key regulator of inflammatory muscle atrophy, supporting its potential as a therapeutic target for sarcopenia.