Brief Bioinform. 2026 Mar 1;27(2):bbag153. doi: 10.1093/bib/bbag153.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is an intractable lung disease that belongs to idiopathic interstitial pneumonia (IIP) with limited therapeutic options. Conventional patient stratification approaches often fail to integrate diverse data modalities, particularly heterogeneous electronic medical records (EMR) containing mixed discrete and continuous values, with omics data, or fail to extract the interpretable many-to-many relationships crucial for precision medicine. We introduce subset binding (SB), a novel unsupervised algorithm that extends fuzzy association rule mining to robustly integrate heterogeneous clinical data (EMR) and omics data. This framework is uniquely designed to identify clinically meaningful patient subgroup patterns and discover associated molecular signatures based on observable symptoms rather than relying on ambiguous conventional diagnostic categories, such as IIPs. Applying SB to a dataset including 602 samples (from 403 IIPs including IPF patients and 39 healthy controls), we successfully identified 20 proteins linked with key IPF clinical features. Network-based pathway analysis nominated tyrosine kinases as critical drug target candidates, leading to the proposal of ponatinib, a multi-kinase inhibitor, as a candidate therapeutic. Functional validation using a TGF-β-induced epithelial-mesenchymal transition (EMT) model confirmed ponatinib's ability to at least partially suppress TGF-β-induced EMT. This inhibitory effect is consistent with the anti-fibrotic mechanism of the existing IPF drug, nintedanib, and reinforces prior evidence supporting ponatinib's anti-fibrotic property. This study demonstrates that SB enables transparent, reproducible, and robust, molecularly defined patient stratification from multimodal patient data. By establishing a data-driven framework that focuses on observation-based rules, this work lays the critical foundation for future prognostic validation and tailored treatment strategies, offering clinically actionable insights and therapeutic discovery in diagnostically ambiguous diseases like IPF, with ponatinib emerging as a compelling repurposing candidate. Significance statement Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with limited therapeutic options. IPF is classified as idiopathic interstitial pneumonia (IIP), but distinguishing it from other similar diseases in IIP is not straightforward. The ambiguities in distinguishing IPF from other IIPs necessitate the identification of molecules associated with specific clinical features, rather than relying on solely on diagnosis. Existing methods for multi-omics data analysis often fail to effectively integrate heterogeneous data - such as EMR (containing mixed discrete and continuous values) and omics - or to extract many-to-many molecular-phenotypic relationships. We developed subset binding (SB), a novel, interpretable unsupervised machine learning method to specifically address these technical limitations by integrating EMR and omics data. Our approach successfully detected proteins in serum extracellular vesicles associated with IPF-related features, highlighted several tyrosine kinases as potential drug targets, and proposed the multi-kinase inhibitor ponatinib as a compelling candidate for drug repurposing. This data-driven framework establishes a scalable and interpretable foundation for biomarker and drug target discovery for intractable diseases whose mechanisms are not fully understood.

PMID:41978386 | PMC:PMC13076932 | DOI:10.1093/bib/bbag153

Cell Rep Med. 2026 Mar 30:102708. doi: 10.1016/j.xcrm.2026.102708. Online ahead of print.

ABSTRACT

Intratumor heterogeneity (ITH) undermines transcriptome-based stratification in intrahepatic cholangiocarcinoma (iCCA). Here, we integrate multi-omics data from multi-region, single-region, and single-cell RNA sequencing cohorts to systematically characterize gene expression ITH. We uncover that immune and stromal heterogeneity are primary drivers of ITH, leading to misclassification of a median 27.8% of tumors by existing subtyping systems. To overcome this, we identify a low-intratumor-heterogeneity/high-intertumor-variability (LIHV) gene set and develop an ITH-insensitive classification system defining five subgroups: inflammatory (SI), metabolic (SII), atypical (SIII-1), immune-silent (SIII-2), and neurodegenerative (SIII-3). These subgroups exhibit distinct clinical outcomes, molecular features, immune landscapes, and therapeutic vulnerabilities. GPRC5A and VTCN1 serve as robust immunohistochemical biomarkers for SI and SIII tumors, while serum CEA and CA19-9 identify inflammatory iCCA. Therapeutically, HSP90 inhibition synergizes with anti-PD1 in inflammatory iCCA, whereas combined anti-PD1 and anti-TIM3 suppresses neurodegenerative iCCA. Collectively, our study provides a robust molecular framework and actionable therapeutic strategies for iCCA.

PMID:41916296 | DOI:10.1016/j.xcrm.2026.102708

Front Oncol. 2026 Feb 25;16:1743620. doi: 10.3389/fonc.2026.1743620. eCollection 2026.

ABSTRACT

Lung cancer remains the leading cause of cancer-related mortality, yet current precision oncology approaches remain overwhelmingly tumor-centric, guided by genomic alterations and immune biomarkers, while largely neglecting the profound impact of aging biology on treatment response. While emerging evidence suggests that aging biology can modify therapeutic benefit and toxicity, its clinical integration remains uneven and largely investigational. In this review, we explicitly distinguish the chronological aging from biological aging to clarify how host biology modifies therapeutic benefit and toxicity. We synthesize mechanistic, translational, and early clinical evidence, while explicitly noting areas where prospective validation is lacking, to reframe personalization of lung cancer therapy through an age-conscious lens. We summarize data indicating that immunosenescence is associated with T-cell exhaustion, myeloid dominance, and extracellular matrix stiffening, features that may contribute to immune-evasive tumor phenotypes and attenuated responses to immune checkpoint blockade in subsets of patients, while pediatric cases, though rare, illustrate how global precision initiatives like iTHER and ZERO enable cautious adaptation of adult therapies. Moving beyond chronological age, we discuss biological age biomarkers, including PhenoAgeAccel, epigenetic clocks, telomere length, and frailty indices, which outperform traditional metrics in predicting risk, resistance, and toxicity, and propose integrating these tools into trial design, screening, and care planning which show promise for risk stratification and toxicity prediction but are not yet validated for routine treatment selection. Looking forward, we outline investigational strategies at the intersection of geroscience and oncology, including immune engineering, senolytics, microenvironmental modulation, and AI-driven multi-omic modeling. Overall, this review argues that biological age represents a critical but still underdeveloped dimension of precision oncology, and highlights key evidence gaps that must be addressed before age-aware personalization can be implemented in routine lung cancer care.

PMID:41821888 | PMC:PMC12975599 | DOI:10.3389/fonc.2026.1743620