Feiyi Xu, Can Zhang, Sihan Wu, Yang Li, Yonggang Chen, Youwei Zhang
Aim: Cisplatin (DDP) represents the first-line chemotherapeutic agent for lung adenocarcinoma (LUAD), but acquired resistance severely limits its efficacy. This study investigated the role of the mitochondria-associated long non-coding RNA (mt-lncRNA) LINC01133 and its mechanisms in cisplatin resistance in LUAD. Methods: LINC01133 expression and subcellular localization were detected through high-throughput mitochondrial RNA sequencing, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and fluorescence in situ hybridization (FISH). By modulating LINC01133 expression, we evaluated its effect on cisplatin resistance and malignant phenotypes. Further, western blotting, enzyme-linked immunosorbent assays (ELISAs), and calcium fluorescent probes were used to analyze how LINC01133 affects the Caspase-1/GSDMD signaling pathway, mitochondrial calcium homeostasis, and mitochondrial function. Finally, in vitro rescue experiments and a xenograft mouse model were conducted to validate the function of LINC01133 and its key targets. Results: LINC01133 expression markedly increased in A549/DDP cells and was enriched in mitochondria. Clinical analysis revealed a difference in LINC01133 expression between LUAD and normal lung tissues, and higher LINC01133 expression was associated with poor patient survival. Functionally, LINC01133 overexpression enhanced cisplatin resistance and malignant phenotypes in A549 cells, whereas its knockdown reversed the resistance phenotype and inhibited malignant behaviors in A549/DDP cells. Mechanistically, cisplatin triggered the Caspase-1/GSDMD pathway to induce pyroptosis. LINC01133 inhibited activation of this pathway, alleviating GSDMD-NT-mediated mitochondrial calcium overload and thereby preserving mitochondrial structural integrity and function, ultimately enhancing cisplatin resistance. Conclusion: LINC01133, a mitochondria-enriched oncogenic lncRNA, promotes cisplatin resistance in LUAD by inhibiting the Caspase-1/GSDMD pathway and maintaining mitochondrial calcium homeostasis and function.