The Role of Estrogen Receptor α in SARS-CoV-2 Infection: Molecular Mechanisms and Innovative Pharmacological Strategies

SARS-CoV-2 spike protein is described as the key viral factor responsible for initiating infection, binding not only to host membrane receptors but also to other proteins unrelated to viral entry, exerting broader biological effects. Among these proteins, estrogen receptor alpha (ERα) has emerged as a novel and unexpected binding partner, due to the presence of LXXLL-like motifs in the spike protein that resemble those of nuclear receptor coactivators (NCOAs). ERα, encoded by the ESR1 gene, is a pleiotropic regulator of cardiovascular, immune, and metabolic homeostasis, and its dysregulation may contribute to the pathophysiology of both post-acute sequelae (PASC) and undesired vaccine-related effects. This PhD thesis investigated the functional role of the Spike-ERα interaction, integrating cellular models, biological assays, cellular imaging, and pharmacological approaches. Our findings showed that spike protein alters ERα localization, promotes proliferative and senescence-associated phenotypes, and disrupts epithelial barrier integrity, alterations that may collectively contribute to chronic inflammation and tissue dysfunction. Importantly, selective estrogen receptor modulators (SERMs) and degraders (SERDs) counteracted many of these effects, suggesting that clinically established endocrine therapies could be repurposed to mitigate spike-related pathology. Overall, the collected evidence positions ERα as a pivotal target of the SARS-CoV-2 spike protein and points to SERMs and SERDs as promising candidates to address its extra-viral effects, thereby expanding the therapeutic landscape for COVID-19 and its long-term sequelae.