Targeting PPARγ-p53 to reprogram intervertebral disc degeneration through ferroptosis and senescence modulation

Ferroptosis and cellular senescence have emerged as key pathological processes driving intervertebral disc degeneration (IDD). Despite advances in minimally invasive treatments, systematic therapeutic strategies targeting these two interconnected mechanisms remain lacking. In this study, we propose a “dual-mechanism targeting strategy” that suppresses ferroptosis in nucleus pulposus cells while simultaneously blocking cellular senescence, thereby delaying degeneration and promoting disc regeneration. Through single-cell transcriptomics and clinical sample analyses, we revealed the coexistence of these mechanisms in IDD and elucidated how they jointly drive disease progression. Mechanistic studies further identified that targeting the PPARγ-p53 signaling axis effectively inhibits ferroptosis and senescence, thereby preserving cellular homeostasis. Based on these findings, we constructed a PPARγ-activating drug delivery system embedded within the ROS-responsive hydrogel, enabling localized and sustained release of Pioglitazone to suppress ferroptosis and senescence. In a rat IDD model, this combined strategy markedly delayed disease progression and promoted structural and functional restoration of the intervertebral disc. Collectively, this targeted dual-mechanism regulatory strategy provides a promising approach for IDD therapy. Targeting the PPARγ–p53 axis with a ROS-responsive pioglitazone hydrogel suppresses ferroptosis and senescence, promoting intervertebral disc repair in a rat degeneration model.