Fhl3, also known as four and a half LIM domain protein 3, belongs to the LIM-only family. It can regulate cell growth and signal transduction, playing significant functions in muscle proliferation, cardiovascular diseases, and tumor biology [1]. It may be involved in pathways like TGFβ, Ras, MAPK, PI3K/Akt/mTOR, etc. [4,6,7].

In muscle-related studies, Fhl3 knockdown in chicken satellite cells promoted their differentiation into myotubes, suggesting it negatively regulates this process [2]. In transgenic mouse models, overexpression of Fhl3 in muscles increased the proportion of fast-twitch myofibers and muscle mass, while knockdown decreased muscle mass and the proportion of fast-twitch myofibers [3]. In bovine skeletal muscle cells, Fhl3 promoted cell proliferation, inhibited differentiation, and affected muscle fiber type expression through the PI3K/Akt/mTOR signaling pathway [7].

In cancer, Fhl3 shows a dual effect. In gastric cancer, its high expression contributed to EMT and chemotherapy resistance via MAPK and PI3K pathways [4]. In glioma, Fhl3 inhibited GSC tumor sphere formation and self-renewal by modulating SOX4 [5]. In pancreatic cancer, Fhl3 promoted invasion and metastasis by preventing the ubiquitination degradation of EMT-associated transcription factors [6].

In conclusion, Fhl3 has diverse functions in muscle development and cancer. In muscle, it affects satellite cell differentiation, muscle fiber type formation, and muscle cell growth. In cancer, it can act as either a tumor suppressor or an oncoprotein, depending on the cancer type. The study of Fhl3 using gene-knockout or transgenic mouse models helps to understand its roles in these biological processes and diseases, providing potential targets for muscle-metabolism-related diseases and cancer treatment.