FHL2 enhances ITGB1-mediated ECM remodeling and cellular stiffness to promote radioresistance in non-small cell lung cancer.

Radiotherapy is a cornerstone treatment for non-small cell lung cancer (NSCLC), but its efficacy is frequently limited by tumor-intrinsic radioresistance. Cellular stiffness and extracellular matrix (ECM) interactions are critical mechanisms underlying this resistance. The adaptor protein four-and-a-half LIM domains 2 (FHL2) has emerged as a key regulator of tumor radioresistance. This study elucidates the role of FHL2 in enhancing radioresistance in NSCLC through ECM remodeling and cellular stiffness. FHL2 was found to promote cell survival, DNA damage repair, and ECM remodeling in response to irradiation, with its interaction with integrin β1 (ITGB1) playing a pivotal role. Depletion of FHL2 significantly reduced cell survival and radioresistance in radioresistant NSCLC cell lines, while FHL2 overexpression upregulated ITGB1 expression. Notably, FHL2 depletion elicited effects comparable to ITGB1 knockdown, suggesting ITGB1 acts as a downstream effector of FHL2. Mechanistically, FHL2 enhances ITGB1-mediated ECM remodeling and cellular stiffness via FAK/MAPK signaling pathways, thereby promoting radioresistance. These findings position FHL2 as a potential biomarker and therapeutic target for overcoming radioresistance in NSCLC, offering a foundation for developing strategies to improve radiotherapy outcomes. This study underscores the critical role of FHL2/ITGB1 axis in tumor resistance mechanisms and highlights its therapeutic potential in NSCLC treatment.