结直肠癌（CRC）在晚期很少能被治愈，强调了探索CRC进展和侵袭机制的重要性。前期研究表明，NLRP12 (NOD样受体家族成员)能够抑制结直肠肿瘤发生，但其精确机制尚不清楚。在这里，我们证明，在Nlrp12缺失小鼠中，侵袭性腺癌的发展与与增殖、基质降解和上皮间质转化（EMT）有关的基因表达升高相关。信号通路分析显示，Nlrp12缺失肿瘤中Wnt/β-catenin通路的激活程度较高，而NF-kB和MAPK通路的激活程度则较低。通过使用Nlrp12条件性基因敲除小鼠，我们证实NLRP12以肠上皮细胞特异性的方式调控肿瘤发生、侵袭性和β-catenin激活。此外，NLRP12缺失使得CRC细胞或器官样体增殖过度。通过蛋白质组研究，我们发现STK38是NLRP12的新型相互作用伴侣，参与了GSK3β磷酸化的抑制，从而导致β-catenin的降解。一致地，NLRP12的表达在小鼠和人类结直肠肿瘤组织中明显减少，而磷酸化GSK3β和β-catenin的表达升高。总而言之，NLRP12是Wnt/β-catenin通路的一种强烈的负调控因子，而NLRP12-STK38-GSK3β信号通路可能是CRC的一个有前景的治疗靶点。

Colorectal cancer (CRC) at advanced stages is rarely curable, underscoring the importance of exploring the mechanism of CRC progression and invasion. NOD-like receptor family member NLRP12 was shown to suppress colorectal tumorigenesis, but the precise mechanism was unknown. Here we demonstrate that invasive adenocarcinoma development in Nlrp12-deficient mice is associated with elevated expression of genes involved in proliferation, matrix degradation, and epithelial-to-mesenchymal transition (EMT). Signaling pathway analysis revealed higher activation of the Wnt/β-catenin pathway, but not NF-kB and MAPK pathways, in the Nlrp12-deficient tumors. Using Nlrp12 conditional knockout mice, we confirmed that NLRP12 regulates tumorigenesis, invasiveness, and β-catenin activation in an intestinal epithelial cell-specific manner. In corroboration, NLRP12 deficiency made CRC cells or organoids hyperproliferative. With proteomic studies, we identified STK38 as a novel interacting partner of NLRP12 involved in the inhibition of phosphorylation of GSK3β, leading to the degradation of β-catenin. Consistently, the expression of NLRP12 was significantly reduced while phospho-GSK3β and β-catenin were upregulated in mouse and human colorectal tumor tissues. In summary, NLRP12 is a potent negative regulator of the Wnt/β-catenin pathway, and the NLRP12-STK38-GSK3β signaling axis could be a promising therapeutic target for CRC.