ROCK1 drives colorectal cancer liver metastasis via PRKCH-mediated bioenergetic reprogramming.

Colorectal cancer (CRC) metastasis, particularly to the liver, is a primary contributor to cancer-related deaths, yet the underlying molecular drivers remain insufficiently defined. This study identifies Rho-associated coiled-coil kinase 1 (ROCK1) as a central regulator of CRC metastatic progression. Analysis of patient samples revealed significantly elevated ROCK1 expression in liver metastases relative to primary tumors. Functional assays demonstrated that ROCK1 depletion impaired CRC cell migration and inhibited hepatic colonization in vivo, while ROCK1 overexpression promoted a metastatic phenotype. Mechanistically, ROCK1 loss led to downregulation of EMT markers, including N-cadherin and β-catenin. Transcriptomic profiling uncovered protein kinase C eta (PRKCH) as a downstream effector of ROCK1, with PRKCH expression markedly reduced following ROCK1 knockdown. Functional silencing of PRKCH suppressed CRC cell motility and disrupted metabolic homeostasis by reducing glycolytic flux and mitochondrial respiration. Conversely, PRKCH overexpression partially restored migration and bioenergetic function in ROCK1-deficient cells. Further investigation identified the ERK2-CREB1 signaling axis as critical for ROCK1-driven PRKCH transcription, with pharmacological or genetic inhibition of ERK2 or CREB1 reducing PRKCH expression. CREB1 binding to the PRKCH promoter was validated using luciferase reporter assays. Collectively, these findings reveal a novel ROCK1-ERK2-CREB1-PRKCH signaling pathway that coordinates EMT and metabolic reprogramming to drive CRC liver metastasis, highlighting PRKCH as a promising therapeutic target in advanced CRC.