CHD1L in cancer and beyond: structure, oncogenic functions, and therapeutic potential

Chromodomain Helicase DNA-binding protein 1-Like (CHD1L) is a chromatin remodeling enzyme increasingly recognized as an oncogenic factor promoting tumor progression and metastatic potential by orchestrating transcriptional programs that drive epithelial-mesenchymal transition (EMT), cytoskeletal remodeling, and metastatic dissemination. In parallel, CHD1L has emerged as a master regulator of tumor cell survival by regulating DNA damage response and repair and enforcing G1 cell cycle progression. Furthermore, CHD1L plays a key role in immune evasion pathways by regulating signaling cascades and by suppressing both apoptotic and non-apoptotic cell death. In particular, CHD1L is a key suppressor of PARthanatos, a caspase-independent mechanism triggered by poly(ADP-ribose) (PAR) polymer fragmentation and apoptosis-inducing factor (AIF) activation. By regulating SPOCK1, MDM2, and TCTP, CHD1L further supports survival under cellular stress. Its overexpression correlates with metastasis, therapy resistance, and poor prognosis across many solid tumors. This review covers CHD1L's structure, oncogenic functions, and developmental origins, and highlights emerging therapeutic strategies that target CHD1L as a druggable vulnerability in cancer.