Programmed cell death in gouty nephropathy: molecular mechanisms and therapeutic implications

Abstract

Gouty nephropathy (GN) is a chronic kidney disorder driven by persistent hyperuricemia; however, its pathogenesis remains under-investigated. Emerging evidence highlights that programmed cell death (PCD) plays a central role in GN, linking disordered urate metabolism to inflammation and renal functional decline. In GN, multiple PCD modalities, including apoptosis, necroptosis, pyroptosis, ferroptosis, and autophagy, are aberrantly activated. These death pathways contribute to tubular epithelial cell loss, interstitial inflammation, and fibrosis, forming an interactive pathological network rather than isolated phenomena. Apoptosis quietly depletes nephrons; necroptosis and pyroptosis mediate membranolytic cell rupture and sterile inflammation; ferroptosis inflicts iron-dependent lipid peroxidation injury; and autophagy, a double-edged sword, can both mitigate and exacerbate damage through its crosstalk with other PCD pathways. Recognizing the PCD network as a core driver of GN opens new avenues for therapy beyond conventional urate-lowering. Targeting key nodes of cell death holds promise to interrupt the self-perpetuating cycle in GN, for example: restoring mitochondrial redox balance to limit apoptosis, inhibiting the RIPK3/MLKL necroptosis cascade, suppressing NLRP3 inflammasome-mediated pyroptosis, modulating iron homeostasis to prevent ferroptosis, or fine-tuning autophagy. In sum, deciphering the molecular interplay of PCD in gouty nephropathy not only deepens our understanding of its pathology but also reveals novel therapeutic opportunities to protect the kidney beyond simply lowering uric acid levels.

Keywords: NLRP3 inflammasome; autophagy; ferroptosis; gouty nephropathy; hyperuricemia; monosodium urate crystals; necroptosis; programmed cell death.