Sepsis is a major disease associated with uncontrolled host response to infections [1]. The lung is highly susceptible to damage during sepsis, and this susceptibility is mainly characterized by pulmonary interstitial edema and inflammatory cells infiltration [2]. This impairs gas exchange and a reduction in oxygen partial pressure within both blood and tissues. Tissue and organ hypoxia can result in death in severe cases [3,4]. Therefore, lung tissues have to frequently exposed to hyperoxia (inspired oxygen concentration exceeding 60 %) to ensure adequate oxygen supply in various tissues and organs [5,6]. However, hyperoxia can exacerbate systemic organ damage in critically ill patients. Recent evidence has demonstrated that exposure to hyperoxia for a specific duration and the presence of hyperoxemia can induce pathological damage, worsen disease conditions, and even pose a life-threatening risk [7,8]. A multicenter, prospective, randomized, controlled clinical trial demonstrated that 100 % FiO2 can increase 28 day mortality of septic shock patients [9]. Furthermore, alveolar capillary permeability is increased in COVID-19 patients and individuals exposed to hyperoxia [10]. However, the underlying mechanisms of oxygen toxicity is poorly understood, with one potential mechanism being the excessive production of reactive oxygen species (ROS) due to hyperoxia and subsequent elevation in oxidative stress, leading to tissue damage. A recent study showed that exposure to hyperoxia for 6 h can significantly elevate intracellular ROS levels in both human mammary epithelial cells and mouse breast cancer cells [11]. The inhibition of ROS production or using antioxidants can mitigate lipopolysaccharides (LPS) or hyperoxia-induced acute lung injury [12,13]. Therefore, suppressing ROS production is a novel therapeutic method for managing hyperoxia-induced lung injury.

Ferroptosis is programmed cell death characterized by unique morphological and metabolic features. Ferroptosis is mainly triggered by iron-dependent ROS and the accumulation of excessive lipid peroxides [14]. ROS is a group of highly reactive oxidative free radicals. Iron can induce lipid ROS generation eventually causing cell death [15]. Acyl-CoA Synthetase Long-Chain Family Member 4 (ACSL4) is a lipid-metabolizing enzyme that facilitates ferroptosis by promoting the esterification of polyunsaturated fatty acids (PUFAs) into acyl-CoA [16]. Cellular glutathione peroxidase 4 (GPx4) catalyzes the removal of lipid hydroperoxides from the cellular membrane using two molecules of glutathione (GSH) as an electron donor, leading to the reduction of lipid hydroperoxides into stable lipid alcohols, thereby inhibiting ferroptosis [17]. Xu et al. reported that the expression of GPx4 is decreased in lung tissues of mice with lung ischemia-reperfusion, accompanied by exacerbated lung injury. However, pretreatment with a ferroptosis inhibitor can alleviate lung injury in mice [18]. In conclusion, ROS accumulation during oxidative stress can induce ferroptosis and GPx4 play an critical role in this process. Ferroptosis is associate with the progression of several diseases, such as severe infection, ischemic organ injury, and cancer [19]. However, it is unclear whether hyperoxia exacerbates sepsis-induced lung injury through ferroptosis.

Nicotinamide mononucleotide (NMN) is a crucial precursor to nicotinamide adenine dinucleotide (NAD+), playing a pivotal role in its synthesis. The pharmacological activity of NMN is associated with its role in NAD+ biosynthesis, thereby augmenting the intracellular levels of NAD+ and exhibiting therapeutic potential for various diseases. As a result, the clinical applications of NMN are progressively expanding. A recent study showed that NMN can restore NAD+ levels and enhance mitochondrial and cardiac function in autophagy-deficient heart and cardiomyocytes [20]. It has been reported that NMN supplementation can activate sirtuin 6 (SIRT6) and sirtuin 7 (SIRT7), which are members of the NAD+-dependent histone deacetylase Sirtuins family, thereby protecting cells from radiation-induced damage [21]. Sun et al. demonstrated that NMN treatment can elevate NAD+ levels in liver cancer cells, leading to apoptosis, autophagy, and cell death via the AMPK/mTOR signaling pathway, thereby impeding liver cancer progression [22]. Furthermore, recent investigations have revealed that NMN can suppress cellular ferroptosis. For instance, NMN can ameliorate chronic heart failure by enhancing lysosomal function and inhibiting mitochondrial dysfunction-induced ferroptosis [23]. However, the effect and mechanism of NMN on hyperoxia-aggravated septic lung injury remain unclear.

Here, we explored the therapeutic value of NMN in sepsis-induced lung injury exacerbated by hyperoxia through ferroptosis inhibition. This was achieved via in vivo and in vitro models. Gene regulation technique confirmed that NMN can ameliorate hyperoxia-aggravated septic lung injury by up-regulating GPx4 through increasing SIRT6, and inhibiting ferroptosis of AECs.