SHP 磷酸化丧失重塑脂质代谢以促进结直肠肿瘤发生

Background: Small Heterodimer Partner (SHP/NR0B2) is a central metabolic regulator that integrates bile acid and lipid signaling with intestinal homeostasis. SHP activity is enhanced by phosphorylation at a conserved threonine residue (Thr-58 in mouse; Thr-55 in human), mediated by PKCζ downstream of FGF19 and bile acid receptor activation. While this modification is known to regulate bile acid and lipid metabolism, its role in colorectal cancer (CRC) is unknown. Methods & Results: To determine how impaired SHP phosphorylation influences colorectal tumorigenesis, we analyzed knock-in mice expressing a phosphorylation-defective SHP mutant (SHP-T58A) in multiple CRC models. To determine how loss of SHP phosphorylation influences cell proliferation, we compared organoids generated from SHP-WT and SHP-T58A mice on both wild-type and Apc Min/+ backgrounds. Across both genotypes, SHP-T58A organoids displayed markedly increased budding, growth rate, and stem-cell-associated gene expression, indicating enhanced intestinal stem cell proliferation. Consistent with this, SHP-T58A mice subjected to AOM/DSS exhibited significantly greater colonic tumor multiplicity and tumor area, accompanied by increased SREBP1 activation, elevated FASN and SCD1 expression, and enhanced lipogenic lipid accumulation within tumors. Even in the acute DSS injury model, SHP-T58A colons showed exaggerated epithelial proliferation and dysregulated metabolic gene expression, suggesting that defective SHP phosphorylation alters epithelial regenerative responses and primes the tissue toward tumor-promoting metabolic states. In human HCT116 cells, CRISPR sgSHP knockout lines reconstituted with SHP-WT or SHP-T58A demonstrated that SHP-T58A drives higher proliferation, colony formation, and migration. Gene expression analyses showed activation of oncogenic and stemness-related programs (LGR5, SOX9, CD44, MYC,MET) together with induction of lipogenic genes (SREBF1, FASN, SCD1). In HCT116 mediated xenografted mice, SHP-T58A group formed significantly larger tumors in NSG mice than their SHP-WT counterparts, accompanied by increased SREBP1 signaling and lipid accumulation. Importantly, in parallel human genomic analyses, we identified SHP mutations located near the Thr-55 regulatory region in individuals with early-onset obesity and early-onset colorectal cancer, suggesting that disruption of this phosphorylation-dependent regulatory module may have broader clinical relevance. Conclusion: Loss of SHP phosphorylation is a key metabolic switch that enhances stemness, activates lipogenesis, and promotes colorectal tumorigenesis in both mouse and human models. SHP phosphorylation status may represent a previously unrecognized metabolic vulnerability in CRC.