A109-25 Npc2 Drives Pulmonary Fibrosis Progression By Disrupting Mitochondrial Cholesterol Homeostasis In Alveolar Type II Cells

Nationale

Pulmonary fibrosis is a progressive and fatal lung disease characterized by irreversible tissue remodeling and respiratory failure. Dysfunction and senescence of alveolar type II (AT2) epithelial cells are increasingly recognized as central drivers of disease progression. However, the spatiotemporal dynamics of AT2 cell metabolic reprogramming and its upstream regulatory mechanisms across the fibrotic course remain poorly understood. Mitochondrial dysfunction has been widely observed in fibrotic lungs, yet its metabolic origins are largely undefined.

Methods

A bleomycin (BLM)-induced mouse model of pulmonary fibrosis was established, and lung tissues were collected at day 3, day 7, and day 21 post-injury. Spatial transcriptomic profiling was performed to construct a spatiotemporal atlas of fibrotic progression. Candidate regulators were identified through cell-type–resolved and spatial neighborhood analyses. Function studies were conducted in vivo and in vitro to assess effects on mitochondrial function, AT2 cell senescence, and fibrotic phenotypes.

Results

Spatial transcriptomic analysis revealed that Niemann–Pick disease type C2 protein (NPC2) was markedly upregulated in AT2 cells as early as day 3 after bleomycin exposure and remained persistently elevated through day 21, suggesting involvement throughout fibrotic progression. Functional studies demonstrated that NPC2 suppression attenuated fibrosis. Mechanistically, excess NPC2 promoted abnormal cholesterol trafficking to mitochondria, leading to mitochondrial dysfunction and induction of AT2 cell senescence.

Conclusions

This study establishes NPC2 as a key metabolic regulator that is persistently activated in AT2 cells during pulmonary fibrosis. By disrupting mitochondrial cholesterol homeostasis, NPC2 promotes epithelial senescence and mitochondrial dysfunction, thereby driving fibrotic progression Targeting NPC2 represents a promising therapeutic strategy and highlights mitochondrial lipid homeostasis as a critical axis in pulmonary fibrosis pathogenesis.

This abstract is funded by: National Natural Science Foundation of China (Number 82070063 and 82270089)