The role of cryptochrome (CRY) in cancer: molecular mechanisms and clock-based therapeutic strategies

Shuzhao Zhang, Xue Chen, Jiayi Li, An'an Xu, Ann M. Bode, and Xiangjian Luo

Circadian rhythms, endogenous ~24-hour oscillations governing physiological, behavioral, and biochemical processes, are ubiquitous across living organisms. Their core generation mechanism relies on transcriptional-translational feedback loops (TTFLs). Within this framework, cryptochrome (CRY) proteins function as critical negative regulators, playing an essential role in sustaining robust circadian rhythmicity. Disruption of circadian rhythms is implicated in diverse pathologies, and CRY exhibits context-dependent roles—acting variably as a tumor promoter or tumor suppressor—during the oncogenesis and progression of distinct cancer types. This review systematically synthesizes current knowledge on CRY’s multifaceted contributions to tumorigenesis across various cancers. Furthermore, it explores the interplay between core clock genes and the tumor microenvironment (TME), alongside emerging chronotherapeutic strategies. The cover symbolically depicts this duality: the bisected clock face represents CRY, with one hemisphere signifying its tumor-promoting functions and the opposite its tumor-suppressive roles. The encircling time zones represent the twelve important markers of tumors, while the universe-like background represents the tumor microenvironment.

This cover is designed by Yinxi Zhou and Jianfeng Jin from Hainan Medical University.