8:2 fluorotelomer alcohol exacerbates doxorubicin-induced cardiotoxicity and chemoresistance via aryl hydrocarbon receptor.

8:2 fluorotelomer alcohol (8:2 FTOH), a persistent environmental pollutant, raises concerns due to its potential health risks. With increasing cancer cases and doxorubicin (DOX) chemotherapy use, PFAS-exposed patients face heightened cardiovascular disease (CVD) and drug resistance risks. However, the mechanisms underlying 8:2 FTOH's impact on DOX-induced cardiotoxicity and resistance remain unclear. Here, we demonstrate that chronic 8:2 FTOH exposure exacerbates DOX-induced cardiac injury by promoting mitochondrial dysfunction and AIM2 inflammasome-mediated pyroptosis via aryl hydrocarbon receptor (AHR) activation. Co-exposure elevated cardiac injury markers (atrial natriuretic peptide [ANP], lactate dehydrogenase [LDH], troponin T [TnT]), mitochondrial Ca²⁺ overload, and ATP depletion, along with pro-inflammatory cytokine release. Mechanistically, 8:2 FTOH bound AHR (Kd=4.42 μM) andsynergized with DOX to induce mitochondrial DNA release, activating the AIM2 inflammasome. Pharmacological AHR inhibition mitigated these effects. Additionally, 8:2 FTOH suppressed immune co-stimulatory molecules (CD80/CD86) in macrophages and cardiac tissues, suggesting a role in DOX resistance. Our findings reveal that 8:2 FTOH enhances DOX cardiotoxicity through AHR-driven mitochondrial damage and pyroptosis while impairing antitumor immunity. This study highlights the dual cardiovascular and chemoresistance risks of environmental 8:2 FTOH exposure, providing insights for therapeutic interventions in vulnerable populations. ENVIRONMENTAL IMPLICATION: 8:2 fluorotalomerol (8:2 FTOH) is a ubiquitous environmental persistent pollutant. It is widely used in many industrial and consumer products, such as textiles and carpets, personal care products, non-stick coatings for cookware, food packaging bags, water-based film-forming foams, automotive, machinery, aerospace, fire protection, medical, and building/construction industries. 8:2 FTOH exposure has been linked to adverse health effects, including cardiovascular disease risk. As the proportion of the global cancer population continues to increase, the number of 8:2 FTOH-exposed cancers treated with the anti-cancer drug doxorubicin (DOX) will inevitably increase. Our study found that long-term exposure to 8:2 FTOH causes cardiac risk, while exacerbating cardiotoxicity and drug resistance during DOX treatment.