Abnormal β‐Hydroxybutyrylation Modification of ARG1 Drives Reprogramming of Arginine Metabolism to Promote the Progression of Colorectal Cancer

Abstract The abnormal arginine metabolism is characteristic of tumor cell metabolism in colorectal cancer (CRC). However, the mechanisms underlying arginine metabolic reprogramming and how altered metabolism in turn enhances CRC tumorigenicity are poorly understood. Protein post‐translational modifications (PTMs) are crucial for regulating protein function, activity, and interactions. Here, the study reports that arginine levels are elevated in CRC, accompanied by the high expression of arginase‐1 (ARG1) but low levels of ARG1 β‐hydroxybutyrylation (Kbhb) and its oncogenic role in CRC in a catalytic‐activity‐independent manner. Mechanistically, low‐level ARG1‐Kbhb‐induced arginine metabolic reprogramming by decreasing the interaction of ARG1 with SLC3A2 in CRC cells inhibits the efflux of arginine, thereby increasing intracellular arginine levels to promote tumorigenicity. P300 is identified as the “writer” of Kbhb. Inducing ARG1‐Kbhb at the Lys313 residue by β‐hydroxybutyrate (BHB) promotes the interaction of ARG1 with SLC3A2, resulting in the efflux of arginine in CRC cells. Together, these findings reveal valuable insights into arginine metabolism reprogramming involving the ARG1‐Kbhb/P300/SLC3A2 signaling axis, thereby bridging the connection between metabolic reprogramming and PTMs, which may shed light on the therapeutic potential of combining BHB with ARG1 inhibitor through the conventional enzymatic role and nonenzymatic metabolic function of ARG1 for CRC.