Pleiotropic pharmacological activities and multiple-organ toxicities of triptolide: a programmed cell death perspective

Triptolide, a bioactive triepoxide diterpenoid extracted from Tripterygium wilfordii Hook. f., has demonstrated broad pharmacological activities and significant toxicities. Mechanistically, triptolide has exerted therapeutic effects by regulating programmed cell death (PCD) through multiple pathways; however, its toxic reactions have been closely associated with this process. This review systematically summarizes the molecular mechanisms by which triptolide regulated various forms of PCD and its application progress in disease treatment, including apoptosis, autophagy, pyroptosis, ferroptosis, cuproptosis, necroptosis, and PANoptosis. A plethora of extant studies have revealed that triptolide exerted a regulatory effect on the PCD networks by intervening in multiple important signaling pathways and their key signaling nodes. Nevertheless, due to its poor target specificity, triptolide has resulted in multi-organ toxicities, which has in turn limited its clinical translation. Nano-delivery systems have explored as a potential strategy to mitigate the toxicity and improve the efficacy of triptolide by enhancing its tissue targeting (Specific nanocarriers can increase LD₅₀ from 0.48 to 0.88 mg/kg). Furthermore, key pharmacodynamic evidences from triptolide's current clinical studies are limited, necessitating the elucidation of precise target sites and the advancement of standardized clinical trials. This review systematically integrates the pleiotropic pharmacological activities and multiple-organ toxicities of triptolide from a PCD perspective, providing novel insights and theoretical references for overcoming its clinical translation barriers.