Exploring Sex Differences in Asthma: The Role of Sex Chromosome Genes in Pathogenesis and ICS/LABA Response

Abstract

Asthma affects over 262 million people worldwide, imposing a substantial global health burden. Asthma is a complex chronic airway disease characterized by airway hyperresponsiveness, variable airflow obstruction, and persistent inflammation, often accompanied by symptoms such as coughing, wheezing, breathlessness, and chest tightness.

Differences in inflammatory regulation between males and females have been attributed to both hormonal and genetic factors, yet the contribution of sex-linked genes remains poorly understood. Given inflammation plays a central role in asthma pathophysiology, the NF-κB signalling pathway serves as a critical regulator of pro-inflammatory cytokine expression. However, whether sex-linked genes influence NF-κB activation and downstream inflammatory responses in asthma remains unclear. This study investigates the roles of RPS4Y1, ZFX and ZFY in modulating inflammation and corticosteroid responsiveness via the NF-κB signalling pathway. ZFX and ZFY are homologous genes on the X and Y chromosome respectively as are RPS4X and RPS4Y. Using gene knockout (KO) models in A549 cells, ZFX KO resulted in a significant increase in IL-6 productions, while ZFY KO and RPS4Y1 KO led to decreased CXCL8 levels. Western blot analysis revealed that ZFX KO cells exhibited increased cytoplasmic accumulation but reduced nuclear translocation of phosphorylated NF-κB following TNF-α stimulation. This suggests chromatin accessibility at inflammatory gene promoters was altered in ZFX KO cells, leading to impaired NF-κB binding and transcriptional dysregulation. Additionally, corticosteroid sensitivity was reduced in ZFX KO cells and increased in RPS4Y1 KO cells, as indicated by higher IC50 values for Budesonide and Budesonide-Formoterol treatment.