《生命科学》 2026, 38(7): 1345-1354
单细胞测序技术下特发性肺纤维化中关键驱动细胞类型的发现
摘 要：
特发性肺纤维化（idiopathic pulmonary fibrosis，IPF）是一种进行性、致死性的间质性肺疾病，患者临床预后极差。纤维化肺组织的细胞组成具有高度异质性，且该异质性具有随疾病进展发生动态变化的特征。与此同时，肺部免疫微环境紊乱、细胞间相互作用异常，均在IPF的发生发展中发挥关键作用。IPF病理特征的高度复杂性，成为当前IPF临床治疗与药物研发面临的核心问题。近年来，单细胞RNA测序（single-cell RNA sequencing，scRNA-seq）技术已成为生命科学领域的重要研究工具之一。该技术能够在单细胞分辨率下实现组织细胞类型的精准分群与功能分析，系统揭示组织微环境中的细胞组成，为解析IPF复杂的细胞类群特征与病理微环境提供了高效的技术手段。本文通过系统梳理scRNA-seq 技术在IPF研究领域的最新文献，重点阐述近年新发现的、在肺纤维化进展中发挥驱动作用的细胞亚群，同时补充介导促纤维化微环境形成的免疫细胞、周细胞、内皮细胞和间皮细胞等非经典效应细胞参与纤维化进程的相关研究突破，明确上述各类细胞在IPF发生和发展中的功能特征与机制。本综述旨在为IPF病理机制的深度解析、疾病关键治疗靶点的筛选，以及后续基础研究向临床转化提供系统的科学依据与理论参考。
通讯作者：芦秀丽 , Email:luxiuli@lnu.edu.cn
Abstract:
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and ultimately fatal fibrosing interstitial lung disease of unknown etiology, pathologically defined as usual interstitial lung disease, with a persistently dismal prognosis. Currently approved antifibrotic agents (nintedanib and pirfenidone) only attenuate disease progression rather than halt or reverse fibrotic remodeling, leaving a critical unmet clinical need for curative therapeutic targets and strategies. The formidable challenges in IPF research stem from the extraordinary complexity of its pathobiology: profound cellular heterogeneity in fibrotic lungs that undergo dynamic lineage reprogramming with disease progression, dysregulated immune microenvironment, and maladaptive intercellular crosstalk that drives the self-sustaining fibrogenic cascade. Unlike bulk RNA sequencing that masks cell-type specific transcriptomic signatures, single-cell RNA sequencing (scRNA-seq) enables unbiased, high-resolution transcriptomic profiling of individual cells, offering an unparalleled tool to decode cellular heterogeneity and the complex tissue microenvironment in IPF. This review systematically synthesizes the cutting-edge breakthroughs of scRNA-seq in IPF research in recent years. We focus on elaborating newly identified, functionally non-redundant cell subpopulations that act as core drivers of IPF progression, including heterogeneous profibrotic myofibroblast subsets and aberrantly reprogrammed alveolar epithelial cell populations. Meanwhile, we summarize scRNA-seq-derived insights into immune microenvironment dysregulation, as well as the pathogenic roles of non-classical effector cells including pericytes, endothelial cells and mesothelial cells during fibrogenesis, with clarification of their lineage origin, functional characteristics and pathological mechanisms. Finally, we propose that scRNA-seq will continue to transform IPF research by identifying novel cell-type-specific therapeutic targets and predictive biomarkers. We further recommend that integrating scRNA-seq with spatial multi-omics and in vitro functional verification will be indispensable to translate these discoveries into clinical practice, ultimately accelerating the development of disease-modifying therapies for IPF.
Communication Author：LU Xiu-Li , Email:luxiuli@lnu.edu.cn
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