FHL2 facilitates LUSC growth and therapy resistance through PI3K/AKT/mTOR activation.

Four and a half LIM domain protein 2 (FHL2) plays a key role in tumorigenesis and progression. This study investigated its involvement in lung squamous cell carcinoma (LUSC). Bioinformatics analysis and immunohistochemistry confirmed that FHL2 is significantly upregulated in LUSC tissues and correlates with poor prognosis. Gain and loss experiments demonstrated that FHL2 promotes LUSC cell proliferation, migration, and invasion in vitro, while xenograft models confirmed its role in tumor growth in vivo. Mechanistically, FHL2 interacts with c-Jun and suppresses its ubiquitination, thereby stabilizing the c-Jun protein, upregulating PDK1 expression, and subsequently activating the PAM signaling pathway. Notably, FHL2 overexpression induced afatinib resistance in LUSC cells, and patients with afatinib resistance exhibited high levels of FHL2 expression. Our results demonstrate that FHL2 promotes LUSC progression and induces afatinib resistance by regulating the PAM signaling pathway. FHL2 may serve as a crucial prognostic marker for the survival outcomes of LUSC patients and a promising therapeutic target for their treatment.