Regulatory mechanisms of programmed cell death in hyperuricaemia and their disease relevance

Abstract

Hyperuricaemia (HUA) is a metabolic disorder that can not only predispose patients to gout but also be associated with renal, cardiovascular, and metabolic diseases. Recent evidence has designated programmed cell death (PCD) as a central event that drives tissue injury and inflammation in HUA. Raised soluble urate and exposure to monosodium urate (MSU) crystals activate separate but shared stress and injury pathways, including apoptosis, pyroptosis, ferroptosis, and necroptosis in concert with dysregulated autophagy. These processes converge through oxidative stress, mitochondrial dysfunction and signalling along the inflammasome–immune axis to influence disease progression. Among these cell death modalities, the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome–mediated pyroptosis is a crucial amplifier of urate-induced inflammation and concomitant cellular injury; ferroptosis also contributes to irreversible organ damage along with impaired autophagy. More importantly, extensive crosstalk among these pathways collectively shapes disease trajectory and outcomes. This Review summarises the main regulatory mechanisms that promote PCD during HUA, with a focus on renal injury, cardiovascular damage and metabolic dysregulation. Distinct from pathway-specific summaries, this Review integrates apoptosis, pyroptosis, ferroptosis and necroptosis together with autophagy-related dysfunction into a unified disease-relevance framework linking urate-associated stress, pathway crosstalk and organ-specific injury in HUA. Current limitations and novel therapeutic targets are also discussed to inform basic mechanistic studies together with potential clinical strategies.