Targeting microglial PANoptosis through AMPK activation: Metformin as a promising therapy for spinal cord injury

Spinal cord injury (SCI) triggers robust neuroinflammation, in which microglial activation and dysregulated programmed cell death exacerbate secondary damage. PANoptosis, a recently defined inflammatory cell death modality integrating pyroptosis, apoptosis, and necroptosis, has been implicated in central nervous system (CNS) injury, yet its cellular specificity and regulation remain unclear. In this study, integrative bioinformatic analyses identified microglia as the predominant PANoptotic cell population after SCI, with PANoptosis inversely correlated with adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway activity. Using metformin, a classical AMPK activator, we demonstrated that pharmacological activation of AMPK suppresses microglial PANoptosis, promotes a shift toward an anti-inflammatory microglial phenotype, and suppresses the associated pro-inflammatory cytokine cascade by inhibiting the nuclear factor κB (NF-κB) signaling pathway. This modulation of the immune microenvironment promotes axonal regeneration, remyelination, and functional recovery in a rat SCI model. Notably, the neuroprotective effects of metformin were abrogated by the AMPK inhibitor compound C (CC), confirming AMPK-dependence. Together, our findings demonstrate that metformin alleviates microglial PANoptosis in an AMPK-dependent manner, promoting tissue repair and functional recovery after SCI. This study uncovers AMPK as a key regulator of microglial PANoptosis and highlights the therapeutic potential of metformin for SCI repair.