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
Integrative single-cell RNA sequencing analysis of publicly available datasets from non-small cell lung cancer and breast cancer is performed to systematically map transcriptional heterogeneity and regulatory networks within the TME, providing a systems-level framework of TME organization.
M. O. Odubote, Chiemeka Elochi Emeribe· bioRxiv· 0 citations
This work discusses recent advances in understanding how this pathway modulates the immune landscape, cancer-associated fibroblasts, and tumor vasculature and outlines how YAP/TAZ drives fibroblast activation, matrix stiffening, and promotes cancer-associated fibrosis.
A structured narrative synthesis of STAT3 regulation in liver fibrosis is provided to 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
This review examines how tumor-derived signals activate IRE1α/XBP1 to upregulate both the autophagy-lysosome pathway (ALP) and ubiquitin-proteasome system (UPS); its crosstalk with inflammatory and metabolic networks; and the therapeutic potential of IRE1α inhibitors, XBP1-directed strategies, and nutritional approaches including arginine.
Guanran Ding, Wang Yang, Yixin Zhao et al.· Biochimica et biophysica act...· 0 citations
