Acute respiratory distress syndrome (ARDS), a severe form of acute lung injury (ALI), can result from various factors such as infection, trauma, shock, drug effects, accidental ingestion, and inhalation of noxious gases[19]. It is characterized by extensive inflammatory cell infiltration in lung tissue and pulmonary edema due to changes in pulmonary vasculature permeability. Based on the Berlin definition, ARDS is classified into 3 categories according to the degree of hypoxemia: mild (PaO2/FiO2 200–300 mm Hg), moderate (PaO2/FiO2 100–200 mm Hg) and severe (PaO2/FiO2 < 100 mm Hg) [29], [17], [26]. Despite decades of research, treatment options for ARDS still remain limited, and supportive therapy with mechanical ventilation is one of the few primary treatment options [13]. However, prolonged and excessive mechanical ventilation can exacerbate the non-infectious inflammatory response in the lungs [14]. Therefore, exploration of more efficient treatment with fewer side effects is needed.

It has been found that ARDS pathogenesis often involves the occurrence of cell death including apoptosis, necroptosis, pyroptosis, and ferroptosis[3], [42]. Receptor-interacting protein kinase 1 (RIPK1) is a key regulator in cell death, exerting its function through either kinase activity or scaffold action[24], [9], [6]. It is worth noting that the kinase activity and scaffolding function of RIPK1 exhibit different functions in mediating cell fate and inflammation [18]. The kinase activity of RIPK1 mediates the programmed cell death pathway (apoptosis or necroptosis), through interacting with either caspase-8 or RIP3 and MLKL, while the scaffold function of RIP1 facilitates the pro-survival (NF-κB) pathway and promotes cell survival [23], [10], [33]. So far, investigation of the diverse roles of RIPK1 in different physiological and pathological contexts has received extensive attention and research in recent years. The kinase activity of RIPK1 has been shown to play key roles in mediating the development of different inflammatory diseases, including neurodegenerative diseases, nonalcoholic steatohepatitis (NASH), cardiovascular diseases and so on[8], [40], [37], [11]. However, regarding the role of RIPK1 in the pathogenesis of ARDS and related mechanisms, it is still not completely understood, and more relevant research is required. Shao et al. reported that pretreatment with Necrostatin-1 (Nec-1), a RIPK1 inhibitor, attenuates the pulmonary inflammatory response and protects the lung from mechanical ventilation injury [32]. However, since Nec-1 was found to be less selective as a RIPK1 inhibitor, has off-target tendencies, and at the same time the micromolar potency and poor metabolic stability (t1/2 < 5 min) of Nec-1 have limited its application. In this study, we chose a more selective, metabolically stable and two potent RIPK1 inhibitors, Nec-1s and RIPA-56, along with RIP1 kinase-inactivated（RipK45A/K45A）mice to explore the involvement of RIPK1 kinase in LPS-induced ARDS, so as to provide new insights to our understanding of ARDS pathogenesis and the development of potential treatment strategies.