Objectives: Fine particulate matter (PM_2.5), a small molecule particulate pollutant, can reach the lungs via respiration and cause lung damage. Currently, effective strategies and measures are lacking to prevent and treat the pulmonary toxicity of PM_2.5. Astaxanthin (ASX), a natural xanthophyll carotenoid, has attracted attention due to its unique biological activity. Our research aims to probe into the prevention and treatment of ASX on PM_2.5-induced lung injury and clarify its potential mechanism. Methods: Sprague-Dawley (SD) rats were given olive oil and different concentrations of ASX orally daily for 21 days. PM_2.5 suspension was instilled into the trachea of rats every two days for one week to successfully develop the PM_2.5 exposure model in the PM_2.5-exposed and ASX-treated groups of rats. The bronchoalveolar lavage fluid (BALF) was collected, and the content of lung injury-related markers was detected. Histomorphological changes and expression of markers associated with oxidative stress, inflammation, iron death, and apoptosis were detected in lung tissue. Results: PM_2.5 exposure can cause changes in lung histochemistry and increase the expression levels of TP, AKP, ALB, and LDH in the BALF. Simultaneously, inflammatory responses and oxidative stress were promoted in rat lung tissue after exposure to particulate matter. Additionally, ASX preconditioning can alleviate histomorphological changes, oxidative stress, and inflammation caused by PM_2.5 and reduce PM_2.5-related ferroptosis and apoptosis. Conclusion: ASX preconditioning can alleviate lung injury after PM_2.5 exposure by inhibiting ferroptosis and apoptosis.

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