CARF, also known as CDKN2AIP and Collaborator of ARF, is a multi-module regulator that plays a crucial role in cell proliferation, acting as a molecular bridge between cellular senescence and carcinogenesis [1,2,5]. It stabilizes the p53-tumor suppressor protein, either in an ARF-dependent or-independent manner, and transcriptionally represses HDM2, which negatively regulates p53 through proteasomal-mediated degradation. Thus, CARF controls the p53-HDM2-p21WAF1 axis to regulate cell proliferative fates [1].

In male CARF knockout mice, fertility is significantly impaired, and they exhibit Sertoli-cell-only (SCO) syndrome phenotypes. Loss of CARF in Sertoli cells leads to decreased GDNF expression, hindering spermatogonial stem cells (SSCs) self-renewal. In undifferentiated spermatogonia, CARF loss impairs their proliferation [3]. Additionally, fatty livers from mice have low CARF expression. Silencing and overexpressing CARF result in higher and lower fat accumulation in HepG2 cells respectively, suggesting CARF dysregulation by excess fat leads to hepatic steatosis [4]. In colorectal cancer, aberrant upregulation of CARF is found in tumor tissues, promoting cancer stemness by activating the ERBB signaling pathway [6].

In conclusion, CARF has essential functions in regulating cell proliferation, spermatogenesis, and lipid metabolism. The study of CARF knockout mouse models has revealed its roles in male infertility, hepatic steatosis, and colorectal cancer, providing insights into the underlying molecular mechanisms and potential therapeutic targets for these disease conditions.