Endogenous metabolite bilirubin suppresses esophageal squamous cell carcinoma by activating PERK-dependent translational repression.

Bilirubin, an endogenous heme catabolite with potent antioxidant properties, has been inversely associated with cancer risk across multiple malignancies; however, its clinical relevance and the underlying molecular mechanisms in esophageal squamous cell carcinoma (ESCC) remain incompletely understood. Here, we retrospectively analyzed a cohort of 2011 patients with ESCC and found that higher serum bilirubin levels were associated with improved overall survival and served as an independent favorable prognostic factor. Mechanistically, physiological bilirubin directly engaged protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) and activated the PERK-eIF2α signaling axis, resulting in translational repression and suppression of ESCC proliferation. This translational repression was associated with altered cell cycle progression in vitro. In xenograft models, bilirubin treatment inhibited tumor growth and was accompanied by increased eIF2α phosphorylation and reduced proliferative activity. Together, these findings demonstrate that higher physiological bilirubin is associated with favorable prognosis in ESCC and bilirubin suppresses tumor progression via PERK-mediated translational repression, providing mechanistic insights into the role of the PERK-eIF2α axis in bilirubin-mediated tumor suppression.