The FHL Protein Family in Cancer: Roles, Dysregulation, and Therapeutic Implications

The four-and-a-half LIM (FHL) protein family, a subgroup of the LIM-only super-family, consists of cysteine-rich cytoskeletal proteins characterized by four-and-a-half LIM domains. These proteins display tissue-specific expression and diverse cellular functions, and accumulating evidence has linked their dysregulation to tumorigenesis. FHL proteins influ-ence key biological processes, including transcriptional regulation, cytoskeletal remodeling, cell proliferation, and signaling pathway modulation, thereby contributing to cancer initiation and progression. Depending on cellular and tissue context, they may function either as tumor suppressors or as oncogenic drivers. Recent studies have highlighted their diagnostic and prog-nostic potential, as aberrant expression of FHL proteins correlates with clinical outcomes in multiple malignancies. Moreover, growing attention has been directed toward their therapeutic relevance, with efforts focusing on targeting upstream regulatory mechanisms to modulate FHL activity. This review provides an integrated overview of the structural and functional features of the FHL protein family, summarizes current understanding of their roles in cancer biology, and discusses their potential as biomarkers and therapeutic targets. By outlining the mechanisms underlying their dysregulation, this work offers new perspectives on the biologi-cal significance of FHL proteins and their implications for cancer research and clinical prac-tice.