Abstract

The pathogenesis of idiopathic pulmonary fibrosis (IPF) involves complex interactions among diverse lung cell types, yet their precise roles remain incompletely understood. Single-cell RNA sequencing (scRNA-seq) offers unprecedented resolution to dissect alterations within specific cell populations, providing critical insights into IPF progression. Intriguingly, the natural compound baicalein has emerged as a potential therapeutic candidate for IPF. To unravel its molecular mechanism and cell-type-specific effects, we conducted a systematic investigation using a bleomycin (BLM)-induced murine IPF model. The results demonstrate that baicalein markedly alleviates pulmonary fibrosis by reducing pathological collagen deposition. Strikingly, scRNA-seq revealed a novel dual-targeting mechanism: baicalein simultaneously suppresses glycolysis in both fibroblasts and macrophages, which is a previously unreported finding. Further analysis uncovered a critical metabolic crosstalk between these cells, where glycolytic activation amplifies pro-fibrotic signaling. By disrupting this interplay, baicalein effectively silences fibroblast-macrophage communication, leading to diminished collagen production. These findings not only elucidate a metabolic-intercellular signaling axis in IPF, but also position baicalein as a promising multi-cellular therapy with translational potential.