Emerging Lysosome Functions in Ferroptosis [Mar. 10, 2026]

1. Targeting ALDH16A1 mediated thioredoxin lysosomal degradation to enhance ferroptosis susceptibility in SMARCA4-deficient NSCLC (Nature Communications, 2025)
Summary: SMARCA4 deficiency, which has been recognized as a poor prognostic factor in non-small cell lung cancer, was shown to confer ferroptosis resistance. This study identified a novel SMARCA4–ALDH16A1–TXN regulatory pathway in which SMARCA4 induces ALDH16A1, thereby increasing ferroptosis susceptibility through lysosomal degradation and functional inhibition of the antioxidant factor thioredoxin.

Highlighted technique: To determine whether ALDH16A1 promotes lysosomal degradation of thioredoxin (TXN), the authors first examined whether TXN is regulated at the RNA or protein level in cells with altered ALDH16A1 expression. They then blocked new protein synthesis and added chloroquine or MG132 to test whether TXN is degraded through the lysosomal or proteasomal pathway. Finally, they visualized TXN and the lysosomal marker LAMP1 by immunofluorescence to assess whether ALDH16A1 loss or restoration changes TXN–lysosome colocalization.

2. Ferroptosis induces heterogeneous death profiles that are controlled by lysosome rupture (Developmental Cell, 2026)
Summary: Ferroptosis is a form of cell death driven by lipid peroxidation, and this study showed that GPX4 inhibition gives rise, within the same treated population, to cells with necrotic features and others with apoptotic features. Importantly, the study identified lysosomal rupture as a key factor that shifts this response toward necrotic outcomes, with glutathione depletion enhancing this shift and cathepsin activity contributing to necrotic cell rupture.

Highlighted technique: To determine whether lysosomal rupture occurs during GPX4 inhibition-induced cell death, the authors used cells expressing the fluorescent reporter GFP-Gal3 and monitored punctate signals that appear upon lysosomal damage. By tracking GFP-Gal3 together with Sytox staining after GPX4 inhibition, they examined whether lysosomal rupture occurs before plasma membrane rupture and whether it differs between cells showing necrotic or apoptotic features.