Fhl2, also known as LIM protein FHL2, is a member of the LIM-only family. As a multifunctional adaptor and scaffolding protein, it can interact with a variety of molecules such as cell surface receptors, kinases, and transcription factors. Fhl2 is involved in numerous functional activities including cell proliferation, apoptosis, adhesion, migration, and gene expression regulation. It participates in multiple signaling pathways like the EGF/EGFR/YAP, ErbB, and Hippo/YAP pathways, and is crucial for normal physiological processes in muscle, cardiac tissue, and many other tissues [1,2,3,4].

Fhl2-knockout (KO) mouse models have been instrumental in understanding its functions. In female mice, Fhl2 deficiency significantly decreased litter size and offspring number, reduced ovarian size, and impaired follicular development by attenuating EGF/EGFR/YAP signaling in ovarian granulosa cells [4]. In arterial medial calcification associated with chronic kidney disease, FHL2-null mice showed that inhibition of FHL2 expression can prevent the transdifferentiation of vascular smooth muscle cells into an osteogenic phenotype and mitigate aortic calcification without harming the skeletal system [5]. In lung adenocarcinoma, knockout of FHL2 in cancer-associated fibroblasts reduced their ability to promote the migration and invasion of lung adenocarcinoma cells, tube formation of endothelial cells, and metastasis in an orthotopic model [6].

In conclusion, Fhl2 plays essential roles in multiple biological processes, especially in tissue development, wound healing, and inflammation. The use of Fhl2 KO mouse models has provided valuable insights into its functions in diseases such as female sub-fertility, arterial medial calcification in chronic kidney disease, and lung adenocarcinoma progression. Understanding Fhl2's functions can potentially lead to new therapeutic strategies for these diseases.