Sulforaphane attenuates oxidative stress, senescence, and ferroptosis induced by cigarette smoke extract in vitro and in vivo via upregulating the expression of SIRT1.

Abstract

Background and purpose: Cigarette smoking induces lung toxicity by triggering oxidative stress, leading to apoptosis, ferroptosis, and senescence. Sulforaphane (SFN), a potent antioxidant, activates the SIRT1 pathway, enhancing cellular stress resistance and survival. This study aimed to evaluate the protective effects of SFN against cigarette smoke extract (CSE)-induced damage in human airway epithelial cells (BEAS-2B) and in mouse lungs, focusing on its role in upregulating SIRT1 expression.

Experimental approach: BEAS-2B cells were treated with CSE and SFN, and cell viability was assessed using the MTT assay. Cellular senescence was assessed using the SA-β-gal assay and the expression of genes associated with senescence (p16 and p21). The expression levels of SIRT1, senescence-associated secretory phenotype (SASP) cytokines (IL-1β, IL-6, IL-8, TNF-α), GPX4, and SLC7A11 were quantified using qRT-PCR. Additionally, ROS production, GSH and MDA levels, and iron content were measured. An emphysema mouse model was induced by intraperitoneal administration of CSE (7.2 mg/kg) alone or in combination with SFN (10.2 mg/kg) over 28 days, and subsequent histopathological changes were evaluated.

Findings/results: Our findings revealed that SFN co-treatment effectively mitigated CSE-induced cytotoxicity, senescence, and SASP cytokine secretion, as well as the pronounced emphysematous changes in lung tissues. Furthermore, SFN reversed CSE-induced downregulation of SIRT1 and upregulation of NF-κB. Notably, SFN also inhibited CSE-induced ferroptosis by increasing GPX4 and SLC7A11 expression while reducing iron and MDA levels.

Conclusion and implications: The findings of the present study demonstrated that sulforaphane offers protective effects against CSE-induced toxicity by mitigating oxidative stress, ferroptosis, and cellular senescence.