IL-32 is defined as a context-dependent integrator of metabolic and inflammatory signaling, whose regulatory network is rewired during hepatocarcinogenesis to promote a sustained pro-inflammatory state.
Abstract
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.
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.
Gautam Kumar, Shailza Singh· Frontiers in Immunology· 0 citations
Hepatocellular carcinoma (HCC) represents a formidable oncological challenge characterized by complex molecular pathogenesis and limited therapeutic outcomes, particularly in the context of liver transplantation. As the sixth most commonly diagnosed cancer and the third leading cause of cancer-related mortality worldwide, HCC poses significant clinical challenges that demand innovative therapeutic approaches. Central to HCC development and progression is a pathogenic triad comprising nuclear factor-kappa B (NF-κB), hypoxia-inducible factor-1α (HIF-1α), and oxidative stress-three interconnected pathways that drive inflammation, angiogenesis, metabolic reprogramming, and cell survival. This comprehensive review examines the molecular mechanisms underlying this triad in HCC pathogenesis across different etiological contexts, including viral hepatitis and non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH). We critically analyse the unique clinical challenges posed by HCC in liver transplantation recipients, particularly the paradoxical requirement for immunosuppression alongside antitumor immunity, and constraints surrounding immunotherapy application. Furthermore, we present CIGB-552, a novel peptide therapeutic targeting COMMD1 (Copper Metabolism MURR1 Domain-containing protein 1), as a promising dual-function agent capable of simultaneously disrupting the pathogenic triad through NF-κB inhibition, HIF-1α suppression, and strategic modulation of oxidative stress via SOD1 regulation. The multimodal mechanism of CIGB-552 offers a theoretically rational therapeutic approach for HCC management in both pre-transplant and post-transplant settings. Clinical validation in the transplantation setting is required.
Xu-Fan Cai, Muqiong Xing, Qianrang Lu et al.· International Journal on Bio...· 0 citations
Introduction Macrophage-driven inflammatory programs and NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome plays a critical role for periodontal tissue destruction; however, the transcriptional regulators that mediate these responses remain unclear. This study therefore examined the role of the microRNA-1260b (miR-1260b)–nuclear factor of activated T-cells 5 (NFAT5) axis in inflammatory macrophage responses relevant to periodontal disease. Methods NFAT5 was identified as a candidate miR-1260b target using integrated bioinformatic screening and investigated through gain- and loss-of-function approaches in RAW264.7 macrophages. Inflammasome-related experiments were performed in J774A.1 macrophages using an LPS/ATP two-signal stimulation protocol. Further analyses included a ligature-induced mouse experimental periodontitis model with local NFAT5 small interfering RNA delivery, macrophage polarization assays in murine bone marrow-derived macrophages stimulated with lipopolysaccharide (LPS) and interferon-gamma (IFN-γ), and validation experiments in human peripheral blood mononuclear cell (PBMC)–derived macrophages. Results Transfection with miR-1260b reduced NFAT5 expression and attenuated LPS-induced nuclear accumulation in macrophages. In vivo analyses showed increased NFAT5 expression in inflamed gingival tissues, whereas local NFAT5 knockdown was associated with reduced NLRP3 and interleukin-1 beta (IL-1β) expression. In J774A.1 macrophages, NFAT5 silencing under LPS/ATP stimulation reduced Nlrp3 and Il1b mRNA expression, together with lower NLRP3 and pro-IL-1β protein levels and reduced IL-1β levels in culture supernatants. Additional in vitro experiments demonstrated reduced M1-associated inflammatory gene expression following NFAT5 silencing. Flow cytometric analysis further showed a reduced proportion of CD86+ macrophage subsets after NFAT5 knockdown, accompanied by decreased pro-inflammatory cytokine production in both murine and human macrophage systems. Discussion These findings identify NFAT5 as a key regulator of inflammasome priming that contributes to inflammatory macrophage polarization in periodontal inflammation and suggest the miR-1260b–NFAT5 axis as a potential target for host-modulatory approaches.
Chikako Hayashi, T. Fukuda, Miyu Shida et al.· Frontiers in Immunology· 0 citations
Inflammation is a pivotal driver of the progression from metabolic dysfunction-associated steatotic liver disease (MASLD) to metabolic dysfunction-associated steatohepatitis (MASH), an aggressive form associated with substantial liver-related mortality. However, the molecular mechanisms underlying the initiation and persistence of liver inflammation remain poorly defined. Here, we demonstrated a previously unrecognized role for hepatic acetyl-CoA synthetase short-chain family member 2 (ACSS2) in MASH, showing that ACSS2 upregulation in patients exacerbates MASH progression by functioning as an epigenetic regulator, independent of its canonical lipogenic role. Mechanistically, ACSS2, in complex with lysine acetyltransferase 5 (KAT5), upregulates allograft inflammatory factor-1 (AIF1) transcription via histone crotonylation, thereby inducing liver inflammation and subsequently resulting in the aberrant accumulation of senescent hepatocytes, which further enhances proinflammatory cytokine production. This ultimately initiates a vicious cycle of chronic inflammation, which directly promotes the progression from simple steatosis to MASH. Thus, our work reveals a mechanistically defined and pivotal role for ACSS2 in promoting the MASLD-to-MASH transition, highlighting its potential as a compelling therapeutic target. Acetyl-CoA synthetase 2 (ACSS2) is known to regulate lipid metabolism. Here the authors identified ACSS2 drives MASH through nuclear translocation and complexes wiht KAT5 to crotonylate histones and activate AIF1.
Xiao Wen, Ke Wu, Mengyao Wang et al.· Nature Communications· 0 citations
Septic acute kidney injury (AKI) is a life-threatening complication with high morbidity and mortality. Despite decades of research, therapeutic options remain limited to supportive care, underscoring the urgent need to decipher the molecular drivers that govern septic AKI. We used a murine LPS-induced septic AKI model and cultured BUMPT cells. miR-378c expression was assessed by qPCR and fluorescence in situ hybridization. Gain- and loss-of-function studies were performed using miR-378c mimics or locked nucleic acid (LNA) inhibitors in vivo and immune-responsive gene 1 (IRG1) overexpression in vitro. Molecular mechanisms were investigated via chromatin immunoprecipitation (ChIP), luciferase reporter assays, western blotting, and immunofluorescence. miR-378c was significantly upregulated in renal proximal tubules after LPS challenge. NF-κB p65 directly bound to the miR-378c host gene promoter and drove its transcription, confirmed by ChIP and NF-κB inhibition with TPCA-1. Overexpression of miR-378c exacerbated kidney dysfunction, tubular apoptosis, and inflammation, while its inhibition conferred protection. IRG1, encoding the immunomodulatory enzyme that produces itaconate, was identified as a direct target of miR-378c. miR-378c suppressed IRG1 expression, and IRG1 overexpression alone reduced LPS-induced apoptosis and proinflammatory cytokine production (IL-1β, IL-6, TNF-α). We define a maladaptive NF-κB/miR-378c/IRG1 axis in septic AKI, where inflammation-induced miR-378c silences a key metabolic protector in tubular cells. Targeting this pathway represents a promising therapeutic strategy to preserve renal function during sepsis.
Lulu Zhou, Xiang Zhou, Hong-Mei Deng et al.· Renal Replacement Therapy· 0 citations
Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a growing global health concern; however, its multiple pathogenic mechanisms remain incompletely understood. The role of the aryl hydrocarbon receptor (AHR) in MASLD is controversial, as it has been described as either pro- or anti-steatotic depending on the experimental context. Through whole-genome expression profiling and RT-qPCR analysis of human liver biopsies from two independent MASLD patient cohorts, we demonstrate that AHR expression and its canonical activity-assessed by CYP1A1 mRNA levels-are inversely correlated with hepatic steatosis. The role of AHR was further investigated in cultured human Upcyte® hepatocytes from different donors treated with a 2:1 oleate:palmitate mixture (0.6 mM) to induce steatosis, in combination with the exogenous AHR agonist β-naphthoflavone (BN, 25 µM) or the endogenous agonist 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE, 25 µM). Activation of AHR resulted in a statistically significant reduction of intracellular lipid levels, as determined by triglyceride quantification and AdipoRed staining. Microarray analysis of AHR-activated human hepatocytes identified IGFBP1 as a robustly induced target gene. Consistently, IGFBP1 expression was diminished in the livers of both MASLD cohorts and positively correlated with AHR expression levels. Furthermore, treatment of human hepatocytes with recombinant IGFBP1, alone or in combination with IGF1, reduced lipid accumulation, supporting IGFBP1 as a potential downstream effector within the anti-steatotic AHR pathway. Collectively, these findings support a role for AHR and its target IGFBP1, as key negative regulators of hepatic lipid accumulation in human hepatocytes and suggest that activation of this pathway may be taken into account in the therapeutic approaches for MASLD.
Marta Del Pozo-Medina, P. Soluyanova, Eugenia Pareja et al.· Archives of Toxicology· 0 citations
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