High-mobility group box 1 (HMGB1), a multifunctional nuclear protein, exists mainly within the nucleus of all mammal eukaryotic cells. It is actively secreted by the necrotic cells as a response to the inflammatory signaling pathway. HMGB1 binds to receptor ligands as RAGE, and TLR and becomes a pro-inflammatory cytokine with a robust capacity to trigger inflammatory response. It is a critical mediator of the pathogenesis of systemic inflammation in numerous inflammatory disorders. Release of HMGB1 is associated with different viral infections and strongly participates in the regulation of viral replication cycles. In COVID-19 era, high HMGB1 serum levels were observed in COVID-19 patients and linked with the disease severity, development of cytokine storm (CS), acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). SARS-CoV-2-induced cytolytic effect may encourage release of HMGB1 due to nuclear damage. Besides, HMGB1 activates release of pro-inflammatory cytokines from immune cells and up-regulation of angiotensin I-converting enzyme 2 (ACE2). Therefore, targeting of the HMGB1 pathway by anti-HMGB1 agents, such as heparin, resveratrol and metformin, may decrease COVID-19 severity. HMGB1 signaling pathway has noteworthy role in the pathogenesis of SARS-CoV-2 infections and linked with development of ALI and ARDS in COVID-19 patients. Different endogenous and exogenous agents may affect release and activation of HMGB1 pathway. Targeting of HMGB1-mediated TLR2/TLR4, RAGE and MAPK signaling, might be a new promising drug candidate against development of ALI and/or ARDS in severely affected COVID-19 patients.

高迁移率族蛋白 1 (HMGB1) 是一种多功能核蛋白，主要存在于所有哺乳动物真核细胞的细胞核内。作为对炎症信号通路的反应，它由坏死细胞主动分泌。 HMGB1 与 RAGE 和 TLR 等受体配体结合，成为一种促炎细胞因子，具有强大的触发炎症反应的能力。它是许多炎症性疾病中全身炎症发病机制的关键介质。 HMGB1 的释放与不同的病毒感染相关，并强烈参与病毒复制周期的调节。在COVID-19时代，在COVID-19患者中观察到高HMGB1血清水平，并与疾病严重程度、细胞因子风暴（CS）、急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）的发展相关。 SARS-CoV-2 诱导的细胞溶解作用可能会因核损伤而促进 HMGB1 的释放。此外，HMGB1 还能激活免疫细胞释放促炎细胞因子并上调血管紧张素 I 转换酶 2 (ACE2)。因此，通过抗 HMGB1 药物（例如肝素、白藜芦醇和二甲双胍）靶向 HMGB1 通路可能会降低 COVID-19 的严重程度。 HMGB1 信号通路在 SARS-CoV-2 感染的发病机制中具有值得注意的作用，并与 COVID-19 患者中 ALI 和 ARDS 的发生有关。不同的内源性和外源性物质可能影响HMGB1途径的释放和激活。靶向 HMGB1 介导的 TLR2/TLR4、RAGE 和 MAPK 信号传导，可能是一种新的有前景的候选药物，可预防严重受影响的 COVID-19 患者发生 ALI 和/或 ARDS。