<scp>ATG4B</scp> is required for <scp>mTORC1</scp> ‐mediated anabolic activity and is associated with clinical outcomes in non‐small cell lung cancer

The complex interplay of metabolic signaling networks is critical to the pathophysiology of lung cancer. The anabolic mTORC1 kinase and catabolic process of autophagy are key among these regulatory pathways. While their relationship has long been viewed as a matter of simple inhibition, with mTORC1 as a negative regulator of autophagy, new evidence suggests that this relationship may be more nuanced than previously described. Here, we demonstrate that an autophagy-related, ATG4B, is required for mTORC1 activity and is associated with negative clinical outcomes in non-small cell lung cancer (NSCLC). Targeting ATG4B in vitro suppresses cell proliferation, protein synthesis rates, and mTORC1 signaling in a cellular model of NSCLC. In contrast, overexpressing the ATG4B protease in healthy models of lung tissue increased mTORC1 kinase activity in healthy lung cell models, indicating that an increase in ATG4B is sufficient to drive cellular anabolic signaling. Finally, we found that ATG4B expression is high in NSCLC patient tumors, is elevated in early-stage cancer, and predicts survival in lung adenocarcinoma patients. Taken together, our results demonstrate that ATG4B is required for anabolic behavior in NSCLC, indicating that the autophagic cascade may be a required input for mTORC1 activity and cellular anabolism in lung cancer. These results have implications for the field of cancer biology more broadly, as they indicate that the far from being a simple target of mTORC1, the autophagic cascade may serve as a requisite input for anabolic signaling, casting new light on the relationship between these processes in cancer pathophysiology. [Correction added on 25 February 2026, after first online publication: 9th sentence has been revised as "Targeting ATG4B in vitro suppresses cell proliferation, protein synthesis rates, and mTORC1 signaling in a cellular model of NSCLC"].