Sepsis is characterized by a systemic inflammatory response to severe infections, affecting multiple organs throughout the body, with the lungs being particularly susceptible, making patients highly prone to acute lung injury (ALI) [1]. The onset of ALI could trigger a cascade of events including pulmonary edema, heightened alveolar permeability, accumulation of inflammatory cells, and widespread alveolar damage, which culminate in the development of acute respiratory distress syndrome (ARDS) [2]. Currently, the standard therapeutic strategies for ALI primarily consist of protective mechanical ventilation and symptomatic supportive care; however, their therapeutic efficacy and long-term prognosis remain suboptimal [3]. Thus, exploring novel compounds against the development of ALI is undoubtedly crucial for enhancing respiratory function and improving the long-term outcomes for patients with ALI.

Emerging evidence has indicated that pyroptosis, characterized by the rupture of the plasma membrane and the subsequent release of cytokines into the extracellular space, is a direct contributor to the cytokine storm associated with ALI [4]. Notably, NOD-like receptor family pyrin domain containing 3 (NLRP3), an intracellular innate immune signaling receptor, plays a pivotal role in inflammasome formation, IL-1β and IL-18 activation, GSDMD cleavage, as well as the initiation of pyroptosis upon recognition of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) [5]. And pharmacological inhibition or genetic ablation of NLRP3 significantly mitigated lung tissue destruction and improved pulmonary function in a murine model of LPS-induced ALI [6], [7], [8]. These findings suggest that targeting NLRP3-mediated pyroptosis may represent a critical therapeutic strategy for ameliorating ALI.

Glycolysis represents a metabolic pathway involving the degradation of glucose to pyruvate, concomitant with the generation of ATP. This process is biphasic in nature. The initial phase involves the transformation of a single glucose molecule into two molecules of triose phosphate. The subsequent phase entails the conversion of these triose phosphates to pyruvate, during which ATP is synthesized. In anoxic conditions, pyruvate is reduced to lactate [9], [10]. Recent investigations have implicated metabolic reprogramming of glucose as a pivotal modulator of NLRP3 inflammasome activation in macrophages [11], [12]. During ALI, the inhibition of glycolysis-mediated NLRP3 inflammasome activation could significantly reduce lung pathological injury [13]. Herein, blocking the process of glycolysis in macrophages may be an effective strategy to combat NLRP3 inflammasome activation and pyroptosis.

Peficitinib is an oral, selective JAK3 inhibitor used for the treatment of rheumatoid arthritis, ulcerative colitis, and psoriasis [14]. Recently, the protective roles of Peficitinib in alleviating solid organ injury were also investigated. For instance, Peficitinib could inhibt mucositis by reducing inflammatory accumulation, alleviating aging, and oxidative stress during 5-fluorouracil-induced intestinal damage [15]. Given that blocking JAK3 could inhibit glycolysis in a STAT3-dependent manner, we speculate that Peficitinib may possess the ability to suppress glycolysis and to prevent ALI. Thus, the present study aims to explore whether Peficitinib pretreatment can relieve LPS-induced ALI and the related mechanisms.