Aug 2026· Frontiers in Immunology· Vol 17· 0 citations· 61 references
Medicine
TL;DR
A systems-level framework is provided that transforms broad observations of inflammation into ranked therapeutic targets and support combined strategies aimed at blocking the IL-6/STAT3–myostatin/SMAD–FOXO1/3–MuRF1/Atrogin-1 axis to mitigate NSCLC-associated sarcopenia.
Abstract
Non-small cell lung cancer (NSCLC) is frequently associated with sarcopenia, a debilitating condition of muscle wasting driven by complex tumor–muscle cross-talk. To unravel the regulatory mechanisms underlying this phenotype, we reconstructed a comprehensive signaling network integrating inflammatory, anabolic, catabolic, and proteolytic pathways. The network was translated into a mechanistic mathematical model using ordinary differential equations, enabling dynamic simulations of pathway activity. Flux analysis revealed that only a limited number of reactions dominate system behavior, with cytoplasmic IL-6 export and SMAD2/3–4 mediated induction of MuRF1 and Atrogin-1 emerging as major control points for muscle protein breakdown. Crosstalk analysis identified these proteolytic regulators as central hubs, integrating signals from inflammatory cytokines, oxidative stress, and transcriptional modulators. Principal component analysis further confirmed that sarcopenic progression is governed by a compact regulatory core, with IL-6/STAT3, myostatin/SMAD, and FOXO/NF-κB pathways converging on MuRF1 and Atrogin-1. Experimental validation using immunofluorescence-based confocal microscopy demonstrated increased expression and altered localization of these ubiquitin ligases in C2C12 cells co-cultured with lung cancer lines, corroborating model predictions. Together, these findings provide a systems-level framework that transforms broad observations of inflammation into ranked therapeutic targets and support combined strategies aimed at blocking the IL-6/STAT3–myostatin/SMAD–FOXO1/3–MuRF1/Atrogin-1 axis to mitigate NSCLC-associated sarcopenia.
Background Interleukin-32 (IL-32) presents a long-standing paradox in liver disease, with markedly elevated expression in hepatocellular carcinoma (HCC) yet a protective role against hepatic steatosis. The absence of a canonical receptor or defined secretory pathway has obscured its biological function. This study aimed to resolve this paradox by delineating the regulatory mechanisms that govern IL-32 activity during hepatocarcinogenesis. Methods We analyzed two in-house prospective cohorts, including a MASLD cohort and a MASLD-associated HCC cohort, integrating matched transcriptomic and metabolomic data. Targeted lipidomics and multi-omics analyses were combined with single-cell and spatial transcriptomics. Key findings were validated using functional assays and gene perturbation models. Results We identified a disease stage-specific transcriptional switch in which noncanonical NF-κB signaling (NFKB2/RELB) replaces canonical NF-κB as the primary activator of IL-32, forming an auto-amplifying inflammatory loop. This switch is enabled by FOXO1, which acts as a pioneer factor to maintain chromatin accessibility at IL32 and NF-κB loci. Functionally, IL-32 is coupled to lipid metabolism through DGAT2; however, this axis becomes uncoupled in HCC, where DGAT2 loss rewires NF-κB/ERK signaling without recapitulating global metabolic remodeling, thereby sensitizing cells to inflammatory activation. Conclusions These findings resolve the functional paradox of IL-32 by revealing a multi-layered regulatory network that reprograms its activity during liver disease progression, and define IL-32 as a context-dependent integrator of metabolic and inflammatory signaling, whose regulatory network is rewired during hepatocarcinogenesis to promote a sustained pro-inflammatory state. Highlights Noncanonical NF-κB (NFKB2/RELB) drives a self-amplifying IL-32 loop in HCC. FOXO1 licenses this switch by maintaining chromatin accessibility at IL32 and NF-κB loci. IL-32 shifts from a metabolic regulator in MASLD to an inflammatory driver in HCC.
Li Na Zhao, Philipp Kaldis, J. B. Andersen· bioRxiv· 0 citations
Tumor progression is driven by dynamic interactions between malignant cells and the tumor microenvironment (TME), yet the regulatory mechanisms governing cellular heterogeneity and intercellular communication remain incompletely characterized. Here, we performed integrative single-cell RNA sequencing (scRNA-seq) analysis of publicly available datasets from non-small cell lung cancer and breast cancer to systematically map transcriptional heterogeneity and regulatory networks within the TME. Using a unified computational pipeline with Seurat v5, SCENIC, and ligand–receptor modeling, we resolved major cellular populations, including malignant epithelial cells, immune subsets, cancer- associated fibroblasts, and endothelial cells, and their transcriptional states. Malignant cells displayed pronounced intratumoral heterogeneity, occupying a continuum of proliferative, metabolic, and invasive phenotypes linked by pseudotime trajectories. Gene regulatory network inference identified STAT3, NF-κB, MYC, and HIF-1α as central hubs coordinating tumor-associated programs. Notably, we uncovered a cytokine-mediated immunoregulatory axis between malignant cells and tumor-associated macrophages, driven by IL6– IL6R and CCL2–CCR2 signaling. Cell–cell communication analysis further revealed coordinated networks supporting immune suppression, inflammation, and angiogenesis. These findings provide a systems-level framework of TME organization and highlight key transcriptional circuits and signaling pathways as promising targets for disrupting tumor– microenvironment crosstalk in precision oncology.
M. O. Odubote, Chiemeka Elochi Emeribe· bioRxiv· 0 citations
The Hippo-Yes-associated protein (YAP)/transcriptional coactivator with a PDZ-binding motif (TAZ) pathway is frequently dysregulated in cancers. Beyond tumor cell-intrinsic functions of this pathway, Hippo-YAP/TAZ signaling exerts profound influences on the tumor microenvironment (TME). In this work, we discuss recent advances in understanding how this pathway modulates the immune landscape, cancer-associated fibroblasts (CAFs), and tumor vasculature. We first examine its roles in shaping tumor immunity through regulation of the expression of cytokines, chemokines, and immune checkpoint molecules by tumor cells. We then outline how YAP/TAZ drives fibroblast activation, matrix stiffening, and promotes cancer-associated fibrosis. Finally, we highlight its reciprocal regulation with vascular endothelial growth factor (VEGF) and other proangiogenic factors that control endothelial proliferation and vessel remodeling. Together, these findings position the Hippo-YAP/TAZ axis as a key orchestrator of the immune, stromal, and vascular components of the tumor niche and a promising target for therapeutic intervention.
Liver fibrosis is a central pathological process driving the progression of chronic liver disease to cirrhosis and involves complex signaling networks across multiple cell types. Signal transducer and activator of transcription 3 (STAT3) serves as a signaling hub that integrates inflammatory, metabolic, and fibrogenic signals and exerts pleiotropic regulatory functions in liver fibrosis. STAT3 structure and subcellular localization provide the scaffold for signal encoding, whereas post-translational modifications (PTMs) alter STAT3 stability, dimerization, localization, transcriptional activity, and protein interactions. These regulatory states are further translated through direct transcriptional control, epigenetic mechanisms, non-coding RNA networks, signaling crosstalk, metabolic reprogramming, and oxidative stress into cell-specific phenotypes within the fibrotic microenvironment. Current evidence most consistently supports a pro-fibrotic role for STAT3 activation in HSC-centered fibrogenic programs, whereas several PTM-dependent, metabolic, and cell-protective mechanisms remain context-restricted or incompletely validated. Herein, we provide a structured narrative synthesis of STAT3 regulation in liver fibrosis, dissect the current status and challenges of targeted therapeutic strategies, and discuss how context-matched STAT3 modulation may inform future anti-fibrotic strategies.
Selinexor (KPT-330), the first oral selective nuclear export inhibitor, simultaneously modulates key signaling pathways, including NF-κB, JAK/STAT, FOXO, Nrf2, and NLRP3, by blocking XPO1-mediated nuclear export, thereby offering a novel multi-target strategy for treating chronic inflammatory diseases. This review systematically integrates existing preclinical and early clinical evidence within the framework of "cytokine signaling networks", focusing on elucidating the molecular mechanisms and biological effects of selinexor in suppressing proinflammatory factor production, mitigating oxidative stress, and regulating inflammatory tissue-remodeling networks. Recent findings further indicate that SINE compounds can remodel proteostasis, including ankyrin repeat and SOCS box-containing protein 8 (ASB8)/Cullin-RING ligase 5 (CRL5)-associated XPO1 degradation and regulation of the ACE2-TMPRSS2-XPO1 coronavirus-entry network. However, current evidence primarily stems from in vitro and animal studies, and randomized controlled trials in human chronic inflammatory diseases are lacking. Moreover, hematopoietic and gastrointestinal toxicities observed in oncology settings suggest a narrow therapeutic window. This review emphasizes a stepwise translational logic from protein turnover and receptor regulation to next-generation XPO1 inhibitors. At present, selinexor is more suitable as a mechanistic tool for exploring the XPO1-inflammation axis, whereas inflammatory-disease translation will require eltanexor or related agents with more favorable tissue distribution and tolerability, together with precisely stratified clinical studies.
Hai Zhang, Xinyi Liu, Yunhua Zhao et al.· International Immunopharmaco...· 0 citations
Cancer cachexia is a multifactorial syndrome of progressive skeletal muscle wasting and functional decline that affects 50-80% of patients with advanced malignancies, frequently overlaps with sarcopenia, and contributes to 22-30% of cancer-related deaths. Effective therapies remain lacking, in part because the driving mechanisms are incompletely understood. Systemic inflammation-particularly interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α)-has long been considered central to muscle wasting, yet cytokine-targeted trials have shown limited efficacy, prompting investigation of additional pathways. Among these, endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) have emerged as candidates, and this review focuses specifically on the IRE1α/XBP1 branch. The rationale rests on three observations from recent preclinical studies: XBP1s activity is increased in cachectic muscle; XBP1s occupies regulatory regions of autophagy-lysosome and ubiquitin-proteasome genes, a direct transcriptional link to protein degradation that distinguishes it from the translation-attenuating PERK and folding-oriented ATF6 branches; and genetic or pharmacological suppression of IRE1α/XBP1 attenuates wasting in these models. We examine how tumor-derived signals activate IRE1α/XBP1 to upregulate both the autophagy-lysosome pathway (ALP) and ubiquitin-proteasome system (UPS); its crosstalk with inflammatory (JAK-STAT3, NF-κB) and metabolic (mitochondrial dysfunction, fatty acid metabolism) networks; the evidence across cancer models and clinical contexts; and the therapeutic potential of IRE1α inhibitors, XBP1-directed strategies, and nutritional approaches including arginine. We frame the ER stress-autophagy axis as a mechanistically plausible, potentially tractable therapeutic target that requires further cross-model and clinical validation.
Guanran Ding, Wang Yang, Yixin Zhao et al.· Biochimica et biophysica act...· 0 citations