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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

PaLMR: Towards Faithful Visual Reasoning via Multimodal Process Alignment

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

By: Yantao Li · Qiang Hui · Chenyang Yan · Kanzhi Cheng · Fang Zhao · Chao Tan · Huanling Gao · Jianbing Zhang · Kai Wang · Xinyu Dai · Shiguo Lian

10 March 2026 at 12:00

arXiv:2603.06652v1 Announce Type: cross Abstract: Reinforcement learning has recently improved the reasoning ability of Large Language Models and Multimodal LLMs, yet prevailing reward designs emphasise final-answer correctness and consequently tolerate process hallucinations--cases where models reach the right answer while misperceiving visual evidence. We address this process-level misalignment with PaLMR, a framework that aligns not only outcomes but also the reasoning process itself. PaLMR comprises two complementary components: a perception-aligned data layer that constructs process-aware reasoning data with structured pseudo-ground-truths and verifiable visual facts, and a process-aligned optimisation layer that constructs a hierarchical reward fusion scheme with a process-aware scoring function to encourage visually faithful chains-of-thought and improve training stability. Experiments on Qwen2.5-VL-7B show that our approach substantially reduces reasoning hallucinations and improves visual reasoning fidelity, achieving state-of-the-art results on HallusionBench while maintaining strong performance on MMMU, MathVista, and MathVerse. These findings indicate that PaLMR offers a principled and practical route to process-aligned multimodal reasoning, advancing the reliability and interpretability of MLLMs.