Tunneling Nanotube‐Mediated Transcellular Autophagy Alleviates Cadmium Induced Hepatocyte Injury

作者：Tao Wang, Li Wang, Jian Sun, Yan Chen, Waseem Ali, Yonggang Ma, Ruilong Song, Xishuai Tong, Jiaqiao Zhu, Yan Yuan, Jianhong Gu, Jianchun Bian, Zongping Liu, Hui Zou · 发表于：Advanced Science · 年份：2025 · DOI：10.1002/advs.202502793 · 被引用次数：3 · 研究领域：Autophagy in Disease and Therapy、Heavy Metal Exposure and Toxicity

Cadmium (Cd) exposure is strongly linked to various diseases and dysregulation of autophagy is a pivotal mechanism in Cd toxicity. Targeted autophagy strategies are promising for the treatment of autophagy dysregulation-related diseases, including Cd poisoning. However, the current understanding of autophagy mechanisms remains limited, hindering the development of effective strategies. Herein, a novel autophagy pathway, transcellular autophagy. Cd triggers this process in hepatocytes, facilitating the transfer of autophagosomes from damaged to healthy cells for degradation. Mechanistically, reactive oxygen species accumulation is a key driver of transcellular autophagy activation, while the disruption of autophagy fusion mechanisms triggers its activation. Notably, Cd-induced transcellular autophagy relies on the tumor necrosis factor, alpha-induced protein 2 (TNFAIP2)-tunneling nanotube (TNT) system. Blocking this system prevents autophagosome transfer and exacerbates Cd-induced autophagosome overload and apoptosis. The findings offer a novel perspective on autophagy, and provide new insights for targeted autophagy strategies to treat Cd poisoning and autophagy dysregulation-related diseases.