Acute lung injury (ALI) presents a significant clinical challenge due to its high mortality rates and the lack of effective treatment strategies. The most effective approaches to treating ALI include disrupting inflammatory cascades and associated inflammatory damage within the lung. Hederagenin was utilized as a core skeleton to design and synthesize 33 hederagonic acid derivatives. Among these derivatives, compound 29 demonstrated potent anti-inflammatory activity without inducing cytotoxicity, inhibiting nitric oxide (NO) release by 78–86 %. Detailed structure-activity relationship studies and the reverse virtual screening of ALI-related targets revealed that compound 29 exhibits a high affinity for the STING protein. Mechanistic studies revealed that compound 29 suppresses macrophage activation, inhibits the nuclear translocation of IRF3 and p65, and disrupts the STING/IRF3/NF-κB signaling pathway, thereby attenuating the inflammatory response. The in vivo administration of compound 29 was sufficient to protect against lipopolysaccharide (LPS)-induced ALI by suppressing the production of inflammatory mediators, including IL-6, TNF-α, and IFN-β, thereby preserving lung tissue integrity. These results substantiate the anti-inflammatory efficacy of compound 29, both in vitro and in vivo, indicating its potential as a promising lead compound in ALI treatment strategies.

急性肺损伤（ALI）由于其高死亡率和缺乏有效的治疗策略而提出了重大的临床挑战。治疗 ALI 最有效的方法包括破坏肺部炎症级联反应和相关的炎症损伤。以常春藤素为核心骨架，设计合成了33种常春藤酸衍生物。在这些衍生物中，化合物29表现出强大的抗炎活性，且不会诱导细胞毒性，可抑制一氧化氮 (NO) 释放 78-86%。详细的构效关系研究和 ALI 相关靶标的反向虚拟筛选表明，化合物29对 STING 蛋白表现出高亲和力。机理研究表明，化合物29抑制巨噬细胞活化，抑制 IRF3 和 p65 的核转位，并破坏 STING/IRF3/NF-κB信号通路，从而减弱炎症反应。体内施用化合物29足以通过抑制炎症介质（包括IL-6、TNF-α和IFN-β）的产生来预防脂多糖（LPS）诱导的ALI，从而保持肺组织的完整性。这些结果证实了化合物29的体外和体内抗炎功效，表明其作为 ALI 治疗策略中有前途的先导化合物的潜力。