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

## TL;DR

ATG4B, a protein involved in autophagy, is linked to aggressive lung cancer growth and poor patient outcomes, and it supports mTORC1 activity, which drives cell growth.

## Contribution

This study reveals that ATG4B is essential for mTORC1 activity and is associated with negative clinical outcomes in non-small cell lung cancer.

## Key findings

- High ATG4B expression in NSCLC tumors correlates with worse survival in lung adenocarcinoma patients.
- Targeting ATG4B reduces cell proliferation, protein synthesis, and mTORC1 signaling in NSCLC models.
- Overexpression of ATG4B increases mTORC1 activity in healthy lung cells, linking autophagy to anabolic signaling.

## Abstract

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”].

The relationship between anabolic and catabolic processes governing lung cancer cell growth is nuanced. We show that ATG4B, an autophagy regulator, is elevated in lung cancer and that high ATG4B is associated with worse patient outcomes. Targeting ATG4B in cells reduces growth, protein synthesis, and mTORC1 activity, demonstrating a new relationship between autophagy regulation and anabolic behavior in lung cancer.