Triptolide-induced Pyroptosis: A Promising Strategy for Cancer Therapy

Triptolide (TPL), a diterpenoid epoxide, exhibits multifaceted anticancer properties, including the induction of diverse Programmed Cell Death (PCD) mechanisms, such as apoptosis, autophagy, pyroptosis, and ferroptosis. Its ability to modulate signaling pathways, transcriptional activity, and interactions with noncoding RNAs underscores its potential as a versatile therapeutic agent. The apoptotic effects of TPL are well-documented across multiple cancer types. Recent evidence highlights TPL’s role in inducing pyroptosis, particularly through the Gasdermin-E (GSDM- E) pathway, which enhances tumor immunogenicity and stimulates antitumor immunity within the tumor microenvironment (TME). By disrupting mitochondrial membrane potential and inflammasome activation, TPL initiates pyroptotic cell death while modulating immune-related pathways, such as the NF-κB/NLRP3 inflammasome axis. Moreover, TPL’s ability to trigger autophagy and ferroptosis independently or in synergy with other PCD pathways enhances its therapeutic promise. The integration of TPL into cancer treatment protocols offers novel strategies, particularly in combination with immunotherapy, by enhancing immune effector responses and suppressing the pro-tumorigenic polarization of tumor-associated macrophages. However, the clinical translation of TPL faces challenges, including toxicity and the need for optimized delivery systems. Advanced research into TPL derivatives and innovative drug delivery frameworks, such as metal-organic frameworks, is crucial for mitigating side effects while preserving therapeutic efficacy. This review underscores TPL’s potential to redefine cancer therapy by harnessing its unique capacity to induce pyroptosis and other PCD forms, paving the way for its inclusion in next-generation oncological treatment paradigms.