慢性炎症和癌症发展之间的联系是众所周知的。炎症性肠病，包括溃疡性结肠炎和克罗恩病，经常促进结肠癌的发展。因此，控制肠道炎症是预防和控制结肠炎相关结直肠癌（CRC）的一种治疗策略。最近，肠粘膜损伤相关分子模式 S100A8 和 S100A9 通过与其模式识别受体 (PRR)（尤其是 TLR4 和 RAGE）相互作用发挥作用，已成为结肠炎症发病机制中的关键角色。我们发现结肠炎和结肠炎相关 CRC 小鼠模型中 S100A8 和 S100A9 的血清水平升高，并且它们与 PRR、TLR4 和 RAGE 的结合显着增加。在这项研究中，我们开发了一种双重 PRR 抑制肽系统 (rCT-S100A8/A9)，该系统由源自 S100A8 和 S100A9 的 TLR4 和 RAGE 抑制基序组成，并与 CT 肽 (TWYKIAFQRNRK) 缀合，用于结肠特异性递送。在人单核细胞 THP-1 和小鼠 BMDM 中，包含 TLR4 和 RAGE 相互作用基序的 S100A8/A9 衍生肽（0.01、0.1、1 μM）剂量依赖性地抑制 S100 与 TLR4 或 RAGE 的结合，并有效抑制 NLRP3 炎性体激活。我们证明 rCT-S100A8/A9 具有适当的药物样特性，包括体外稳定性和 PK 特性以及药理活性。在DSS诱导的急、慢性结肠炎小鼠模型中，注射rCT-S100A8/A9（50 μg·kg -1 ·d -1，连续一定天腹腔注射）可显着提高存活率并减轻结肠病理损伤。在AOM/DSS诱导的结肠炎相关结直肠癌（CAC）小鼠模型中，注射rCT-S100A8/A9（50 μg·kg -1 ·d -1，腹腔注射）可增加体重，减少远端结肠的肿瘤负荷，并显着减轻组织学结肠损伤。在携带奥沙利铂耐药性 CRC 异种移植物的小鼠中，注射 rCT-S100A8/A9（20 μg/kg，腹腔注射，每 3 天一次，持续 24-30 天）可显着抑制肿瘤生长，同时肿瘤组织中 EMT 相关标记物减少。我们的结果表明，针对 S100-PRR 轴可改善结肠炎症，从而凸显该轴作为结肠炎和结直肠癌的潜在治疗靶点。

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The link between chronic inflammation and cancer development is well acknowledged. Inflammatory bowel disease including ulcerative colitis and Crohn’s disease frequently promotes colon cancer development. Thus, control of intestinal inflammation is a therapeutic strategy to prevent and manage colitis-associated colorectal cancer (CRC). Recently, gut mucosal damage-associated molecular patterns S100A8 and S100A9, acting via interactions with their pattern recognition receptors (PRRs), especially TLR4 and RAGE, have emerged as key players in the pathogenesis of colonic inflammation. We found elevated serum levels of S100A8 and S100A9 in both colitis and colitis-associated CRC mouse models along with significant increases in their binding with PRR, TLR4, and RAGE. In this study we developed a dual PRR-inhibiting peptide system (rCT-S100A8/A9) that consisted of TLR4- and RAGE-inhibiting motifs derived from S100A8 and S100A9, and conjugated with a CT peptide (TWYKIAFQRNRK) for colon-specific delivery. In human monocyte THP-1 and mouse BMDMs, S100A8/A9-derived peptide comprising TLR4- and RAGE-interacting motif (0.01, 0.1, 1 μM) dose-dependently inhibited the binding of S100 to TLR4 or RAGE, and effectively inhibited NLRP3 inflammasome activation. We demonstrated that rCT-S100A8/A9 had appropriate drug-like properties including in vitro stabilities and PK properties as well as pharmacological activities. In mouse models of DSS-induced acute and chronic colitis, injection of rCT-S100A8/A9 (50 μg·kg-1·d-1, i.p. for certain consecutive days) significantly increased the survival rates and alleviated the pathological injuries of the colon. In AOM/DSS-induced colitis-associated colorectal cancer (CAC) mouse model, injection of rCT-S100A8/A9 (50 μg·kg-1·d-1, i.p.) increased the body weight, decreased tumor burden in the distal colon, and significantly alleviated histological colonic damage. In mice bearing oxaliplatin-resistant CRC xenografts, injection of rCT-S100A8/A9 (20 μg/kg, i.p., every 3 days for 24–30 days) significantly inhibited the tumor growth with reduced EMT-associated markers in tumor tissues. Our results demonstrate that targeting the S100-PRR axis improves colonic inflammation and thus highlight this axis as a potential therapeutic target for colitis and CRC.