Osteoarthritis (OA) is a degenerative joint disease which is highly prevalent worldwide. However, no therapy for blocking OA pathogenesis is available currently. In this study, chondroitin sulfate (CS) E oligosaccharides were prepared and we identified disaccharide as the functional unit showing the strongest anti-complement activity and screened out complement C5 as its target in the complement system. We determined that CS-E disaccharide produced anti-inflammatory effects to treat OA by regulating the complement system: it inhibited the formation of complement-dependent complexes such as the membrane-attack complex (MAC) by targeting C5 and suppressed MAC-induced protein expression and the activation of downstream MAPK and NF-κB signaling pathways accordingly. By identifying CS-E disaccharide which could be regarded as a complement regulator or inhibitor exhibiting high anti-complement activity and revealing its OA-alleviating mechanism, this study not only provides a new strategy for OA treatment and drug development, but also potentially offers a promising C5 target therapy for other associated diseases.

骨关节炎（OA）是一种退行性关节疾病，在世界范围内非常流行。然而，目前尚无阻断 OA 发病机制的疗法。在本研究中，我们制备了硫酸软骨素 (CS) E 寡糖，我们将双糖鉴定为显示最强抗补体活性的功能单元，并筛选出补体 C5 作为其在补体系统中的靶点。我们确定CS-E二糖通过调节补体系统产生抗炎作用来治疗OA：它通过靶向C5抑制补体依赖性复合物如膜攻击复合物（MAC）的形成并抑制MAC诱导的蛋白质表达并相应地激活下游 MAPK 和 NF-κB 信号通路。