Radiation-Induced Lung Damage (RILI), a extreme complication following thoracic radiotherapy, considerably compromises affected person restoration and high quality of life [1], [2]. A multicenter retrospective examine carried out in 2024 involving 783 lung most cancers sufferers reported a RILI incidence of 31.4% [3], underscoring its scientific significance. This excessive incidence not solely considerably diminishes sufferers’ high quality of life but in addition weakens the therapeutic results as a consequence of constraints on radiation dosage, thereby hindering the profitable implementation of complete most cancers remedy plans. The pathogenesis of RILI begins with the “reactive oxygen species (ROS) storm” triggered by radiation [4], [5]. Extreme ROS, together with radiation, results in DNA harm and oxidative harm to biomolecules, together with lipids and proteins [6], [7], [8], leading to mobile dysfunction [9]. Quite a few research have demonstrated that the pyroptosis mediated by the NOD-like receptor protein 3 (NLRP3) inflammasome in epithelial cells is an important mechanism within the development of lung harm [10], [11], [12], [13], [14], [15], [16]. This inflammatory programmed cell loss of life is carefully related to ROS [17], [18], [19]. Radiation-induced ROS prompts the NLRP3 inflammasome, selling caspase-1 activation. Lively caspase-1 cleaves pro-interleukin (IL)-1β (pro-IL-1β), pro-interleukin (IL)-18 (pro-IL-18), and Gasdermin D (GSDMD). The cleaved N-terminal fragment (GSDMD-N) accumulates within the cell membrane, forming oligomeric pores, finally resulting in cell pyroptosis [20], [21], [22], [23], [24], [25] and the discharge of pro-inflammatory mediators that additional exacerbate tissue harm [26], [27]. As RILI progresses, ROS can even activate fibroblasts, selling collagen synthesis and deposition, thereby driving the transition from irritation to fibrosis [28], [29], [30]. These processes finally end in structural reworking and practical impairment of lung tissue, doubtlessly advancing to irreversible pulmonary fibrosis. These findings recommend that ROS performs a central regulatory position within the cascading processes of DNA harm, pyroptosis activation, inflammatory response, and fibrotic development [8], [31]. Given the pivotal position of ROS, a great radioprotective agent ought to possess the great functionality to successfully mitigate oxidative stress, inhibit native inflammatory responses, and regulate pyroptosis-related pathways. Nonetheless, the present scientific remedy for RILI primarily depends on corticosteroids and amifostine. Whereas corticosteroids have anti-inflammatory results, they might induce immunosuppression and enhance the chance of an infection [32]. Amifostine affords some radioprotective results, however roughly 28% of customers expertise opposed reactions similar to hypotension [33]. These limitations limit the broad and secure software of current remedy strategies, thus creating a necessity for efficient and safer multi-targeted methods to forestall and deal with RILI, to enhance the radiotherapy tolerance and general high quality of lifetime of sufferers with thoracic tumors.
All through long-term organic evolution, sure organisms have developed important radiation resistance, offering inspiration for novel radioprotective methods. For instance, tardigrades are recognized for his or her excessive environmental tolerance, enabling them to resist radiation doses which are deadly to most life kinds [34], [35]. The antioxidants secreted by tardigrades can successfully scavenge radiation-induced free radicals, mitigating oxidative harm [36]. Equally, cockroaches additionally exhibit good radiation resistance, in a position to endure comparatively excessive radiation doses [37], [38], [39], probably attributable to their environment friendly antioxidant protection mechanisms that remove dangerous free radicals produced by radiation. [40], [41]. Furthermore, the normal Chinese language medication Periplaneta americana extract (PAE) is a posh combination containing varied bioactive compounds and has been clinically utilized within the remedy of ulcers and wounds [42], [43], [44]. Its efficacy in selling cell restore and proliferation has been nicely documented [44], [45], [46]. Research have proven that PAE accommodates small molecules similar to amino acids, peptides, nucleosides, fatty acids, alkaloids, and phenolic compounds, in addition to macromolecules together with proteins, polysaccharides, peptides, and nanoparticles. These parts possess antioxidant and anti inflammatory properties, promote cell migration, cut back fibrosis, and contribute to tissue restore, suggesting their potential position within the prevention and remedy of RILI [47], [48], [49], [50], [51], [52], [53], [54], [55], [56], [57], [58], [59], [60].
Repurposing current medication has change into an necessary avenue in modern drug improvement. Constructing on this, we transformed the generally used oral PAE formulation into an aerosol inhalation type for RILI remedy. Aerosol inhalation, as a non-invasive pulmonary supply methodology, successfully bypasses the first-pass impact [61], [62], enhancing drug retention in lung tissue, growing the native drug focus, lowering systemic opposed reactions, and bettering affected person compliance [63], [64]. In vitro experiments demonstrated that PAE successfully removes varied ROS similar to 1,1-diphenyl-2-picrylhydrazyl (DPPH), •O₂–, and •OH, lowering the prevalence of radiation-induced DNA double-strand breaks (DSBs). Concurrently, it downregulates the expression ranges of inflammatory components (TNF-α, IL-1β, IL-6) and inhibits the activation of the NLRP3 inflammasome, caspase-1 cleavage, and GSDMD processing, thereby blocking the radiation-induced pyroptosis. These findings point out that PAE exerts radioprotective results by eliminating free radicals, lowering DNA harm, and inhibiting pyroptosis and inflammatory responses. In vivo experiments additional verified the technique: nebulized PAE considerably alleviated acute pulmonary irritation in RILI, as evidenced by diminished pro-inflammatory components and inhibited inflammatory cell infiltration. Moreover, downregulating reworking progress factor-β (TGF-β) expression inhibited collagen deposition, successfully blocking the development of fibrosis. Importantly, PAE diminished the activation of pyroptosis-related proteins in lung tissues, suggesting that its protecting impact is expounded to the inhibition of pyroptosis. This PAE aerosol inhalation technique, impressed by naturally radiation-resistant organisms, displays a multi-fold protecting impact of “scavenging ROS, lowering DNA harm, inhibiting pyroptosis, and blocking irritation and fibrosis.” This naturally impressed, drug repurposing strategy offers new insights for the prevention and remedy of radiation-induced ailments and holds important promise for scientific translation (Scheme 1)
