Tunneling Nanotube‐Mediated Transcellular Autophagy Alleviates Cadmium Induced Hepatocyte Injury

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.