The latest asthma biology highlights epithelial alarmins such as TSLP, along with IL-4/IL-13 signaling and IgE pathways, as core drivers, guiding targeted biologic therapies like omalizumab, anti-IL-5/IL-5R, and anti-IL-4Rα antibodies, with tezepelumab offering benefits across eosinophil statuses including low counts.

Asthma remains a global health crisis, affecting roughly 300 million people and presenting significant morbidity, mortality, and economic burden, especially in low- and middle-income countries.

Epigenetic alterations contribute to airway remodeling and memory, suggesting potential reprogramming of airway cells toward a less inflammatory state using epigenetic drugs or miRNA/siRNA approaches, though clinical translation is still in early stages.

Traditionally, asthma therapy centers on inhaled corticosteroids and LABAs, but many patients remain inadequately controlled, with corticosteroid side effects and adherence challenges, and non-T2 phenotypes require alternative strategies.

GWAS has identified about 150–200 asthma risk loci, with notable signals at 17q12–21 (ORMDL3, GSDMB) and 5q (IL-33, IL1RL1, IL4R); multiancestry analyses enhance discovery and improve polygenic risk scores, especially in non-European populations.

Noncoding RNAs, including miRNAs and lncRNAs, modulate asthma inflammation; miR-155 and miR-21 generally promote inflammation, while other RNAs influence Th2 differentiation, with miRNA-based therapies and inhaled siRNAs targeting IL4Rα or TSLP under exploration.

For T2-low asthma, macrolides reduce exacerbations, while optimal therapies are still being defined; early-stage work includes small-molecule inhibitors (JAK-STAT, kinase modulators) and gene/cell therapies.

There is a shift from SABA-only relief to anti-inflammatory strategies, notably ICS and the ICS-formoterol AIR/SMART approach, which reduce exacerbations and improve outcomes even in mild asthma.

Severe asthma, representing about 5–10% of cases, remains highly burdensome and heterogeneous, with eosinophilic and nonatopic/neutrophilic endotypes and complications from remodeling, mucus plugging, and comorbidities.

Biomarkers (eNO, blood eosinophils, periostin, breath VOCs) and integrative omics are refining personalized therapy and monitoring, supported by machine-learning to predict responses.

GWAS findings point to causal genes through eQTLs and functional studies, linking risk variants to gene expression changes in airway cells and pathways like TSLP, IL-33/ST2, and IgE regulation.

Epigenetic modifications link environment and gene expression, with DNA methylation changes identified in epithelial and immune genes; HDAC2 downregulation links to corticosteroid resistance, suggesting strategies to restore chromatin balance.