Current perspectives on natural and pharmacological interventions for combating drug-induced pulmonary toxicity

Drug-induced pulmonary toxicity (DIPT) is a serious and often underappreciated complication that can emerge in patients receiving a wide variety of prescribed drugs, from cytotoxic chemotherapy agents and antiarrhythmics to immunomodulatory compounds. Four agents, in particular methotrexate (MTX), cyclophosphamide (CPA), bleomycin (BLM), and amiodarone (AMI) have the most extensive body of evidence documenting their pulmonary adverse effects, with each capable of producing distinct injury patterns that nonetheless share overlapping features. The mechanisms driving DIPT are far from simple; multiple pathways converge to produce the damage, including oxidative stress, dysregulated inflammatory responses, various modes of programmed cell death (apoptosis, pyroptosis, and ferroptosis), and activation of pro-fibrotic cascades most notably TGF-β1/Smad2/3, NF-κB, and the NLRP3 inflammasome. Standard treatment options for early drug withdrawal, corticosteroids, and supportive care are frequently inadequate, and a significant proportion of patients are left with persistent pulmonary fibrosis long after the causative drug has been stopped. This review offers a thorough examination of the epidemiology, risk determinants, pathological features, diagnostic criteria, and molecular underpinnings of DIPT as caused by MTX, CPA, BLM, and AMI. Going further, it assembles a structured, evidence-grounded compilation of the pharmacological and natural agents that have shown protective potential in experimental DIPT models. Four summary tables covering a combined total of 74 protective interventions are presented, detailing experimental designs, induction protocols, and mechanistic targets. The striking range of strategies assessed spanning small-molecule antioxidants and plant-derived polyphenols to repurposed established drugs highlights the growing understanding that DIPT's mechanistic complexity calls for multi-targeted therapeutic solutions. Taken together, this review integrates available preclinical and clinical data into a practical framework for developing rational lung protection strategies against drug-induced injury.