Lysosomal Integrity Drives Ferroptosis Susceptibility [Apr. 28, 2026]

Lysosomes regulate intracellular degradation and membrane integrity, and recent studies have revealed their roles in ferroptosis by influencing lipid peroxidation and iron metabolism. These lysosomal functions are important for understanding how ferroptosis is controlled. One study showed that GPX4 inhibition causes heterogeneous ferroptotic death, with necrotic and apoptotic-like deaths occurring in parallel, and that lysosomal lipid peroxidation, rupture, and cathepsin involvement promote the switch toward propagating necrotic death. Another study identified NINJ2 as a LAMP1-interacting lysosomal factor that maintains membrane integrity, limits labile iron leakage, and suppresses ferroptosis sensitivity. These findings highlight lysosomal membrane integrity as a regulator of ferroptosis progression and susceptibility. 

1. Ferroptosis induces heterogeneous death profiles that are controlled by lysosome rupture (Developmental Cell, 2026)

Summary: This study shows that GPX4 inhibition-induced ferroptosis produces heterogeneous death profiles within cell populations, with necrotic and apoptotic-like deaths occurring in parallel, and that necrotic death is strongly associated with ferroptosis propagation. Mechanistically, ferroptotic stress induces lipid peroxidation at lysosomal membranes, leading to lysosome rupture and cathepsin involvement that promotes necrotic cell death and its spread to neighboring cells, highlighting the central role of lysosomes in ferroptosis propagation.

Highlighted technique: To determine whether lysosome rupture is linked to necrotic ferroptosis, the authors used live-cell imaging with GFP-Galectin 3, a reporter that forms puncta when damaged lysosomes expose luminal glycans to the cytosol. They also used C11-BODIPY with lysosome staining dye to examine lipid peroxidation at lysosomal membranes, connecting lysosomal lipid peroxidation to lysosome rupture and necrotic ferroptosis propagation.

2. Nerve Injury-Induced Protein 2 preserves lysosomal membrane integrity to suppress ferroptosis (eLife, 2026)

Summary: This study reveals that NINJ2, originally identified as a nerve injury–induced cell adhesion molecule, also functions as a lysosome-associated regulator that interacts with LAMP1 and helps maintain lysosomal membrane integrity, thereby limiting the leakage of reactive labile iron and preserving ferritin stability. Loss of NINJ2 promotes lysosomal membrane permeabilization, ferritin degradation, and expansion of the labile iron pool, ultimately sensitizing cells to RSL3- and erastin-induced ferroptosis and linking lysosomal homeostasis to iron-dependent cell death.

Highlighted technique: To examine whether loss of NINJ2 disrupts intracellular iron homeostasis, the authors treated control and NINJ2-knockout cells with ferric ammonium citrate as an iron source. They then measured intracellular iron levels using an iron assay kit and showed that NINJ2-deficient cells exhibited a marked increase in intracellular iron.

Solutions for Lysosome Experiments
Need to visualize lysosomal ferrous iron in your experiments? Lyso-FerroRed enables selective detection to support ferroptosis studies.