The role of LYCAT in EGFR-TKI resistance, NSCLC progression, and smoking-induced lung cancer.

e20021 Background: Non-small cell lung cancer (NSCLC) makes up 85% of lung cancer cases, often with epidermal growth factor receptor (EGFR) mutations, targeted by tyrosine kinase inhibitors (TKIs) like Erlotinib and Osimertinib. Resistance arises from mutations, pathway alterations, and epithelial-mesenchymal transition (EMT). Lysocardiolipin acyltransferase (LYCAT), a mitochondrial enzyme in cardiolipin remodeling, promotes NSCLC proliferation, migration, and EMT, but its role in TKI resistance remains unclear. Hypothesis:We hypothesize that LYCAT overexpression drives EGFR-TKI resistance through EMT regulation, contributing to NSCLC progression and smoking-induced lung cancer. Methods: LYCAT expression was evaluated in drug-resistant (ER/OR) and parental H358, H2170, and PC9 NSCLC cell lines using Western blotting, qRT-PCR, and immunofluorescence. siRNA-mediated LYCAT knockdown in H358ER cells assessed its role in resistance. Immunohistochemistry correlated LYCAT expression with NSCLC stages and smoking status. Results: LYCAT protein was upregulated 3.8-fold in H358ER and 7.6-fold in PC9ER cells (p < 0.05). qPCR showed a 4.2-fold increase in these cells (p < 0.01). Immunofluorescence revealed increased nuclear/cytoplasmic LYCAT in H358ER (1.6-fold) and PC9ER (1.5-fold). Late-stage tumors showed higher LYCAT expression (75%) than early-stage (45%; p < 0.01), with smokers having elevated expression (68% vs. 34%; p < 0.001). Conclusions: LYCAT mediates EGFR-TKI resistance, NSCLC progression, and smoking-related lung cancer through EMT and tumorigenicity regulation. Targeting LYCAT may offer therapeutic solutions for TKI resistance and improve patient outcomes.