PANoptosis as a Potential Therapeutic Target in Drug-Induced Liver Injury: A Narrative Review

Xinru Zhang,1 Zhipin Zhou,1 Zhuohua Xie,2 Jieyi Chen,1 Yanting Deng,2 Yibin Fang,1 Jiasheng Deng,2 Xiaoxue Ye1 1Liuzhou People’s Hospital Affiliated to Guangxi Medical University, Guangxi, 545006, People’s Republic of China; 2School of Pharmacy, Guangxi University of Chinese Medicine, Nanning, Guangxi, 530200, People’s Republic of ChinaCorrespondence: Zhipin Zhou, Liuzhou People’s Hospital Affiliated to Guangxi Medical University, 8 Wenchang Road, Cheng Zhong District, Liuzhou, Guangxi, People’s Republic of China, Tel +86− 18776921947, Email gxzhouzhipin@126.comAbstract: PANoptosis is a recently characterized form of programmed cell death defined by the coordinated regulation of pyroptosis, apoptosis, and necroptosis mediated by the multi-protein PANoptosome complex, a phenomenon that cannot be fully explained by any individual pathway. The initiation of PANoptosis relies on the assembly and activation of the PANoptosome, a process that has been closely linked to the onset and progression of multiple disorders, including inflammatory and neurodegenerative diseases, cancer, and pulmonary conditions. However, the contribution of PANoptosis to drug-induced liver injury (DILI) has not been thoroughly evaluated. DILI is a frequently encountered clinical adverse drug reaction, and its development is strongly associated with hepatocyte death. Therefore, this review aims to summarize the molecular mechanisms underlying PANoptosis and the assembly of the PANoptosome complex, elucidate the interactions among apoptosis, necroptosis, and pyroptosis, and assess the potential involvement of PANoptosis in DILI. Furthermore, investigating natural products that inhibit PANoptosome assembly or target key regulators such as ZBP1, AIM2, and NLRP3 to modulate PANoptosis may offer promising therapeutic opportunities for the management of DILI.Keywords: drug-induced liver injury, PANoptosis, PANoptosome, therapeutic targets