Multi-omics integration identifies APOE as a metabolic regulator of macrophage-fibroblast crosstalk in idiopathic pulmonary fibrosis

By: Bing Bai · Le Chang · Zhi Cheng · Yingjie Wang · Chenfeng Hua · Yonghai Feng · Wenfei Zhao

2 September 2026 at 18:00

Front Immunol. 2026 Aug 18;17:1904638. doi: 10.3389/fimmu.2026.1904638. eCollection 2026.

ABSTRACT

BACKGROUND: Aberrant tissue repair and relentless fibroblast activation are hallmark features of idiopathic pulmonary fibrosis (IPF). Although IPF and Alzheimer's disease (AD) share underlying aging-related pathologies, including immune and metabolic dysregulation, the putative genetic mechanisms linking AD susceptibility to pathogenic macrophage remodeling in the fibrotic niche are not fully established.

METHODS: We performed a two-sample Mendelian randomization (MR) analysis to assess the genetic association and potential causal relationship between AD and IPF. Shared hub genes were identified via protein interaction networks. To characterize macrophage heterogeneity and intercellular crosstalk within the IPF microenvironment, we interrogated scRNA-seq data (GSE122960) utilizing Monocle 3 and CellChat algorithms. The functional essentiality of APOE was evaluated bridging computational virtual knockout (scTenifoldKnk) with laboratory in vitro assays. Specifically, downstream transcriptomic shifts and fibroblast activation capacities were validated using APOE-silenced THP-1 macrophages and a Transwell co-culture model with MRC-5 cells.

RESULTS: MR estimates indicated that genetic liability to AD is associated with a lower risk of developing IPF. Integrated profiling identified the lipid-metabolism gene APOE as a central hub, specifically enriched in lung macrophages. Pseudotime modeling captured a pathogenic bifurcation in IPF, where macrophages evolve toward a terminal state marked by profound oxidative phosphorylation defects and massive SPP1 secretion. These SPP1+ macrophages primarily activate fibroblasts via CD44 and integrin signaling axes. Furthermore, both virtual simulations and in vitro THP-1 experiments demonstrated that loss of APOE function triggers the hyperactivation of complement (C1QA) and antigen-presentation (HLA-DR) pathways. Co-culture assays ultimately confirmed that APOE ablation in macrophages strongly exacerbates myofibroblast differentiation (elevated α-SMA and collagen I) in adjacent MRC-5 cells.

CONCLUSION: APOE functions as a vital metabolic barrier against pro-fibrotic macrophage polarization in the lung. Disruption of this specific lipid metabolic network is strongly associated with SPP1-driven fibroblast activation and local immune imbalance, providing a theoretical framework that strictly warrants future in vivo investigation to determine its clinical relevance.

PMID:42682427 | PMC:PMC13529525 | DOI:10.3389/fimmu.2026.1904638

Pan-neurodegeneration proteomics reveals disease subtypes and molecular signatures

Cell

By: Him K. Shrestha · Huan Sun · Jay M. Yarbro · DongGeun Lee · Danting Liu · Erming Wang · Meghan McReynolds · Nan Zhang · Boer Xie · Shu Yang · Kaiwen Yu · Suresh Poudel · Yuxin Li · Zuo-Fei Yuan · Dehui Kong · Minghui Wang · Zhen Wang · Mingming Niu · Hong Wang · Masihuz Zaman · Ju Wang · David R. Vanderwall · Yu Sun · Zhiping Wu · Ping-Chung Chen · Bing Bai · Anthony A. High · Júlia Faura · Chunyu Liu · David A. Bennett · Erik C.B. Johnson · Nicholas T. Seyfried · Allan I. Levey · Vahram Haroutunian · Geidy E. Serrano · Thomas G. Beach · Michael DeTure · Takahisa Kanekiyo · Ronald C. Petersen · Guojun Bu · Pamela J. McLean · Dennis W. Dickson · Rosa Rademakers · Gang Yu · Xusheng Wang · Bin Zhang · Junmin Peng

23 March 2026 at 08:00

A pan-neurodegeneration atlas built from multilayer, deep proteomics of 2,279 brain samples across 6 major diseases integrates whole proteome, detergent-insoluble proteome, and posttranslational modifications to enable intra- and inter-disease comparisons to reveal disease-specific subtypes and dysregulated pathways, while identifying shared changes such as GPNMB upregulation and NPTX2 downregulation.

CosyAccent: Duration-Controllable Accent Normalization Using Source-Synthesis Training Data

cs.AI, q-bio.NC updates on arXiv.org

By: Qibing Bai · Shuhao Shi · Shuai Wang · Yukai Ju · Yannan Wang · Haizhou Li

24 February 2026 at 13:00

arXiv:2602.19166v1 Announce Type: cross Abstract: Accent normalization (AN) systems often struggle with unnatural outputs and undesired content distortion, stemming from both suboptimal training data and rigid duration modeling. In this paper, we propose a "source-synthesis" methodology for training data construction. By generating source L2 speech and using authentic native speech as the training target, our approach avoids learning from TTS artifacts and, crucially, requires no real L2 data in training. Alongside this data strategy, we introduce CosyAccent, a non-autoregressive model that resolves the trade-off between prosodic naturalness and duration control. CosyAccent implicitly models rhythm for flexibility yet offers explicit control over total output duration. Experiments show that, despite being trained without any real L2 speech, CosyAccent achieves significantly improved content preservation and superior naturalness compared to strong baselines trained on real-world data.

Reading view