Metabolic Reprogramming and ILC2 Plasticity in Obesity-related Asthma.

Abstract

Obesity-related asthma is a major clinical challenge defined by its unique pathology and resistance to corticosteroids. Here, we reframe this disease through the lens of tissue-specific "maladaptive plasticity" of group 2 innate lymphoid cells (ILC2s). We propose a central dichotomy: in the obese lung, mechanical transduction synergizes with metabolic inflammation to induce a HIF-1α-mediated glycolytic shift in ILC2s. Conversely, in visceral adipose tissue (VAT), chronic metabolic stress drives ILC2 functional exhaustion, suppressing cytokine secretion. This pulmonary glycolytic shift fuels acetyl-CoA accumulation and subsequent epigenetic remodeling, which locks ILC2s into a pathogenic ILC1/ILC3-like phenotype, thereby driving the non-Th2 inflammation characteristic of obesity-related asthma. Furthermore, we describe how systemic metabolic stress propagates through the "adipose-pulmonary" and "gut-pulmonary" axes, which includes neutrophil extracellular traps (NETs) and glucocorticoid receptor isoform imbalances. Collectively, these pathological changes establish a refractory network of corticosteroid resistance, a primary factor contributing to treatment failure in obesity-related asthma. Based on these findings, we propose a novel therapeutic framework termed "Metabolic Resuscitation". This strategy shifts the focus from conventional immunosuppression to restoring cellular homeostasis by targeting key metabolic checkpoints and epigenetic drivers. This review provides a new mechanistic framework for understanding obesity-related asthma and offers a rationale for developing therapies to reverse treatment resistance.