Circadian dysfunction regarding Hepatic and Renal cancer depending on ARNTL, PER2 and PER3- A Review

Circadian dysfunction plays a critical role in the onset and progression of hepatic and renal cancers, driven by the dysregulation of key circadian clock genes, including ARNTL, PER2, and PER3. In hepatocellular carcinoma, disrupted circadian rhythms affect cell cycle control, DNA repair, and metabolism, facilitating tumor growth and metastasis. ARNTL, a central circadian regulator, is often silenced in HCC due to promoter hypermethylation, impairing pathways related to cell proliferation and differentiation. Tumor-suppressor genes PER2 and PER3 are also downregulated, promoting resistance to therapy and poor prognosis through disrupted apoptosis and altered metabolic regulation. Research suggests restoring circadian function could inhibit HCC progression, with chronotherapy emerging as a potential strategy to enhance treatment outcomes.
In renal cancers, especially clear cell renal cell carcinoma, circadian dysfunction involves altered ARNTL expression, which interacts with hypoxia-inducible factors (HIFs) to drive angiogenesis and metabolic changes. ARNTL dysregulation fosters tumor development, while downregulation of PER2 and PER3 contributes to unchecked cell proliferation, genomic instability, and disrupted circadian regulation of pathways like Wnt/β-catenin signaling. These disturbances exacerbate oxidative stress and inflammation, fueling tumor progression. Targeting circadian pathways offers promising opportunities for diagnosis, prognosis, and treatment, with the potential to improve patient outcomes by restoring circadian homeostasis.