Reorganización del Eje Hippo-Inflamación-Polcomb Impulsada por ROS en Modelos de Epitelio Pulmonar 2D y 3D por PFOA

Perfluorooctanoic acid (PFOA), a persistent organic pollutant and prominent member of the per- and polyfluoroalkyl substances (PFAS) family, continues to raise global concern due to its bioaccumulation and potential for chronic human exposure. While hepatic and systemic toxicities of PFOA are well documented, its effects on lung epithelial integrity, particularly at environmentally relevant concentrations, remain incompletely understood. In this study, we investigated the cellular and molecular responses to PFOA in human alveolar lung epithelial cells (A549) cultured under both 2D submerged monolayer and 3D air-liquid interface (ALI) conditions, representing systemic and barrier-relevant exposure models. Cells were exposed to 10-1000nM PFOA for 24h to assess changes in pro-inflammatory mediators, including transcription factors-NF-κB and STAT3, pattern recognition receptors (TLR4 and RAGE), cytokine/chemokine production (IL-6, IL-8, CCL2, CCL5), and damage-associated molecular patterns (HSP70, HMGB1). PFOA also appeared to trigger translational stress responses, including stress granule and P-body formation, along with alterations in Hippo signaling via YAP/TAZ overactivation. PFOA-challenged cells exhibited activation of Polycomb Repressive Complexes and associated silencing histone marks (H3K27me3, H2AK119Ub), along with HDACs and SIRT family members, indicative of a redox-driven Polycomb-mediated gene silencing program. Oxidative stress was identified as the central driver of epigenetic and Hippo pathway disruptions, as observed in cells pre-exposed to 1 mM N-acetylcysteine (NAC). Despite these molecular alterations, epithelial cell migration capacity remains unaffected under acute exposure. Our results provide key mechanistic insights into PFOA-mediated disruption of redox homeostasis, immune signaling, and epigenetic plasticity in A549 cells, as well as identifying biomarkers for future biomonitoring efforts and studying regulatory frameworks.