The liver is the most common site for colorectal cancer (CRC)–associated metastasis. There remain unsatisfactory medications in liver metastasis given the incomplete understanding of pathogenic mechanisms. Herein, with an orthotopic implantation model fed either regular or high-fat diets (HFD), more liver metastases were associated with an expansion of conjugated bile acids (BAs), particularly taurocholic acid (TCA) in the liver, and an increased gene expression of Na⁺–taurocholate cotransporting polypeptide (NTCP). Such hepatic BA change was more apparently shown in the HFD group. In the same model, TCA was proven to promote liver metastases and induce a tumor-favorable microenvironment in the liver, characterizing a high level of fibroblast activation and increased proportions of myeloid-derived immune cells. Hepatic stellate cells, a liver-residing source of fibroblasts, were dose-dependently activated by TCA, and their conditioned medium significantly enhanced the migration capability of CRC cells. Blocking hepatic BA uptake with NTCP neutralized antibody can effectively repress TCA–triggered liver metastases, with an evident suppression of tumor microenvironment niche formation. This study points to a new BA–driven mechanism of CRC–associated liver metastases, suggesting that a reduction of TCA overexposure by limiting liver uptake is a potential therapeutic option for CRC—associated liver metastasis.

Endometriosis is a chronic inflammatory disorder affecting approximately 10% of reproductive-age women, yet non-hormonal therapeutic options remain limited. This study investigates the role of the TLR4/NF-κB/NLRP3 inflammasome axis in endometriosis pathogenesis and evaluates the therapeutic potential of pharmacologic TLR4 inhibition. Ectopic endometriotic tissues, eutopic endometrium, and peritoneal fluid were collected from 15 patients with ovarian endometriosis and 15 control subjects. The endometriotic epithelial cell line 11Z was stimulated with LPS and ATP with or without the TLR4 inhibitor TAK-242. A murine endometriosis model was established in wild-type C57BL/6 and TLR4⁻/⁻ mice treated with TAK-242. Expression of TLR4, p-p65, NLRP3, caspase-1, cleaved caspase-1 (p20), GSDMD-N, IL-1β, PCNA, and CD31 was assessed by qPCR, Western blot, IHC, and ELISA. Ectopic lesions showed significantly elevated TLR4/NF-κB/NLRP3/IL-1β signaling compared with eutopic and control endometrium (all p < 0.05). Peritoneal fluid IL-1β was increased in patients, indicating a localized pelvic inflammatory response. In vitro, TAK-242 suppressed LPS/ATP-induced NF-κB/NLRP3 activation, pyroptosis, and IL-1β secretion (p < 0.05). Furthermore, the NLRP3-specific inhibitor MCC950 confirmed the essential role of NLRP3 inflammasome activation in IL-1β maturation. In vivo, TLR4 deletion or TAK-242 treatment reduced lesion weight, PCNA proliferation, and CD31 microvessel density (all p < 0.05). TLR4 inhibition blocks NF-κB nuclear translocation and subsequent inflammasome activation, suggesting a potential role in attenuating inflammation and angiogenesis. The TLR4/NF-κB/NLRP3 axis may drive endometriosis progression by linking innate immunity, inflammasome activation, pyroptosis, with possible involvement in angiogenesis warranting further investigation. Pharmacological inhibition of TLR4 attenuates lesion growth, supporting TLR4 as a promising non-hormonal therapeutic target for endometriosis.