WCLC 2025 - Posters & ePosters-P2.02.03 Ferroptosis-Induced SUMO2 Lactylation Counteracts Ferroptosis by Enhancing ACSL4 Degradation in Lung Adenocarcinoma

P2.02.03 Ferroptosis-Induced SUMO2 Lactylation Counteracts Ferroptosis by Enhancing ACSL4 Degradation in Lung Adenocarcinoma

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This study investigates the interplay between lactylation, a novel post-translational modification involving lactic acid, and ferroptosis—a regulated cell death mechanism marked by reactive oxygen species production, lipid peroxide accumulation, and intracellular iron elevation—in lung adenocarcinoma (LUAD). Utilizing metabolomic profiling and metabolic library screening in LUAD cell lines (A549 and PC9), the authors identified lactic acid elevation as a contributor to ferroptosis resistance.<br /><br />Proteomic analyses revealed that ferroptosis induces lactylation at the lysine 11 (K11) site of the small ubiquitin-like modifier SUMO2 (SUMO2-K11la), a modification that inhibits ferroptosis by regulating the stability of the lipid metabolism enzyme ACSL4. Specifically, SUMO2-K11la reduces ACSL4 sumoylation, leading to its degradation and thereby counteracting ferroptosis. This study is the first to report SUMO2-K11 lactylation and demonstrate crosstalk between lactylation and sumoylation.<br /><br />To exploit this mechanism therapeutically, the researchers designed a highly specific cell-penetrating peptide (CPP) targeting SUMO2-K11la. This peptide effectively inhibited SUMO2-K11la in LUAD cells, sensitizing them to ferroptosis inducers (RSL3, IKE) and chemotherapy (cisplatin), as shown by decreased cell viability and increased lipid reactive oxygen species. The study employed multiple methodologies, including lactylation proteomics, co-immunoprecipitation, immunofluorescence, sumoylation proteomics, lipid peroxidation assays, and viability tests to validate findings.<br /><br />In conclusion, the study reveals that SUMO2-K11la serves as a key ferroptosis resistance mechanism in LUAD by promoting ACSL4 degradation and that targeting this lactylation with a CPP can potentiate ferroptosis and chemotherapy efficacy. These findings provide a novel therapeutic avenue for overcoming treatment resistance in lung adenocarcinoma.

Asset Subtitle

Guangyao Shan

Meta Tag

Speaker Guangyao Shan

Topic Tumor Biology – Preclinical Biology

Keywords

lactylation

ferroptosis

lung adenocarcinoma

SUMO2-K11la

ACSL4 degradation

ferroptosis resistance

cell-penetrating peptide

chemotherapy sensitization

lipid peroxidation

post-translational modification