IL-24 steps out of the shadows as a central regulator of liver disease

Interleukin-24, a secreted cytokine that spent decades in the shadow of its famous tumor-killing reputation, is now emerging as a central molecular player across the entire spectrum of liver disease. A comprehensive review published in Molecular Biology Reports by Jiawei Cui, Yukai Chen, Chao Sun and Yuemin Nan traces the journey of this IL-10 family member from its original identification as a melanoma differentiation gene to its current status as a candidate therapeutic target in hepatocellular carcinoma, acute liver injury, liver fibrosis and metabolic dysfunction-associated steatotic liver disease. The review, which synthesizes evidence primarily from in vivo and in vitro experiments, argues that IL-24 has graduated from bystander to key player in hepatic pathology, and it lays out the molecular circuitry that might one day be exploited clinically.

The story begins in 1995, when subtraction hybridization identified a novel gene called melanoma differentiation-associated gene-7, or mda-7, whose expression was modulated during human melanoma differentiation, growth and progression. Subsequent work revealed that the encoded protein, later renamed interleukin-24, is a secreted cytokine belonging to the IL-10 family, and it behaves as a tumor suppressor: it induces apoptosis selectively in cancer cells, inhibits angiogenesis, and modulates antitumor immunity. Structural biology has clarified how the cytokine engages its receptors. IL-24 binds a heterodimeric receptor complex composed of IL-22R1 and IL-20R2, and crystal structures of the labile complex of IL-24 with the extracellular domains of IL-22R1 and IL-20R2 have revealed the molecular interface that underlies signaling through JAK-STAT pathways, chiefly STAT3, as well as MAPK and PI3K-AKT cascades. This receptor usage places IL-24 in the IL-20 subfamily, whose members share overlapping biology in epithelial tissues and inflammatory disease.

The liver, as the review emphasizes, is a unique immunotolerant organ that must maintain metabolic homeostasis while continuously responding to insults ranging from viral infections and toxic substances to metabolic stress. Early hepatology-focused work showed that the murine liver is a potential target organ for IL-19, IL-20 and IL-24, and that type I interferons and lipopolysaccharide regulate the expression of IL-20R2, one of the cytokine’s receptor chains. This established that hepatic cells can both produce and respond to IL-24, setting the stage for the mechanistic studies that followed. What makes the new review particularly valuable is its systematic dissection of IL-24 biology in non-neoplastic hepatopathies, an area the authors describe as less defined than the cytokine’s relatively well-characterized functions in hepatocellular carcinoma.

In hepatocellular carcinoma, the evidence is now extensive. Lentivirus-mediated MDA-7/IL-24 expression inhibits the proliferation of hepatocellular carcinoma cells, and the cytokine suppresses tumor adhesion and invasive potential in hepatocellular carcinoma cell lines. Combining IL-24 with Notch1 downregulation inhibits invasion and migration of hepatocellular carcinoma cells, while miR-203a-3p.1 targets IL-24 to modulate hepatocellular carcinoma cell growth and metastasis, revealing a microRNA axis that tumors may exploit to escape the cytokine’s influence. In patients with hepatitis B virus-related hepatocellular carcinoma, IL-24 limits tumor-infiltrating T helper 17 cell responses, suggesting that the cytokine shapes the tumor immune microenvironment and not just the tumor cells themselves. Interleukin-24 also inhibits the growth of hepatoma cells in vivo, and engineered mutants such as RGD-mda-7 elicit potent antitumor effects by targeting the integrin receptor of tumor cells.

The most technically inventive strand of this research program involves oncolytic virotherapy. Oncolytic adenoviruses engineered to express IL-24 selectively induce apoptosis in hepatocellular carcinoma cell lines, suppress metastasis, and enhance the effect of doxorubicin on xenograft tumors. Interferon-alpha enhances the antitumor activities of oncolytic adenovirus-mediated IL-24 expression in hepatocellular carcinoma, and an oncolytic adenovirus expressing the HAb18 and interleukin-24 genes exhibits enhanced antitumor activity in hepatocellular carcinoma cells. Gene-viro-therapy strategies have combined IL-24 with TRAIL in dual-regulated oncolytic adenoviral vectors, and cancer targeting gene-viro-therapy specific for liver cancer has used alpha-fetoprotein-controlled oncolytic adenovirus expression of SOCS3 and IL-24, exploiting the hepatoma-specific AFP promoter to restrict therapeutic gene expression to malignant cells. Recombinant adenovirus IL-24-Bax promotes apoptosis of hepatocellular carcinoma cells in vitro and in vivo, and oncolytic adenovirus SG600-IL24 selectively kills hepatocellular carcinoma cell lines. Beyond adenoviruses, oncolytic Newcastle disease virus carrying the IL-24 gene exerts antitumor effects by inhibiting tumor growth and vascular sprouting, exploiting the selectivity of Newcastle disease virus for apoptosis-resistant cells, and oncolytic vaccinia virus carrying IL-24 has shown efficacy against hepatocellular carcinoma. A phase I study of intratumoral injection of mda-7 in patients with advanced carcinoma demonstrated the clinical and local biological effects of this approach, providing early clinical grounding for the platform.

Turning to non-neoplastic liver disease, the review highlights a striking intracellular protective mechanism. An intracellular XBP1-IL-24 axis dismantles the cytotoxic unfolded protein response in the liver, meaning that IL-24 produced within hepatocytes can alleviate endoplasmic reticulum stress, the cellular strain that arises when misfolded proteins accumulate in the endoplasmic reticulum. Building on this, interleukin-24 protects against liver injury in mouse models, including models of acute liver injury such as acetaminophen-induced hepatotoxicity, where the cytokine reduces hepatocyte death and lowers serum alanine aminotransferase and aspartate aminotransferase levels. The unfolded protein response machinery, involving sensors such as PERK and effectors such as CHOP and eIF2alpha, sits at the center of this hepatoprotective action, and IL-24’s ability to modulate it positions the cytokine as a candidate intervention for acute and chronic liver injury driven by toxic and metabolic stress.

In liver fibrosis, IL-24 modulates hepatic stellate cell activation, the process by which quiescent pericyte-like cells become myofibroblast-like collagen producers, and it influences proinflammatory cytokine release during fibrotic progression. The fibrosis story has an instructive parallel in the IL-22 literature: interleukin-22 induces hepatic stellate cell senescence and restricts liver fibrosis in mice, demonstrating that IL-20 subfamily and related cytokines can restrain the fibrogenic program of activated stellate cells. IL-24’s receptor chains, IL-22R1 and IL-20R2, are shared with IL-22, which helps explain why the two cytokines converge on stellate cell biology. By modulating the activation state of hepatic stellate cells and the inflammatory milieu in which they operate, IL-24 may slow the transition from chronic injury to cirrhosis.

Metabolic dysfunction-associated steatotic liver disease represents perhaps the most active frontier. Current evidence suggests that IL-24 affects hepatocyte autophagy and metabolic reprogramming in this condition, thereby potentially mitigating disease progression. Intracellular IL-24 ameliorates lipid metabolic disorders in metabolic dysfunction-associated steatohepatitis by restoring the autophagy-lysosome pathway, the cellular waste-disposal system whose failure permits toxic lipid accumulation in steatotic hepatocytes. In mouse models fed high-fat or high-fat high-fructose diets, IL-24’s influence on autophagy, involving regulators such as mTOR, AMPK and the transcription factor TFEB, links the cytokine to the lysosomal machinery that clears damaged organelles and lipid droplets. This metabolic angle connects IL-24 to the broader family biology, since interleukin-22 alleviates metabolic disorders and restores mucosal immunity in diabetes, suggesting a family-level role in metabolic homeostasis that the liver shares with other organs.

The review is candid about limitations. Most of the evidence in non-neoplastic hepatopathies derives from cell culture and mouse experiments, and human validation remains sparse. The cytokine’s pleiotropy cuts both ways: IL-24 promotes atopic dermatitis-like inflammation through driving MRSA-induced allergic responses, and the IL-13/periostin/IL-24 pathway causes epidermal barrier dysfunction in allergic skin inflammation, demonstrating that the same cytokine can be pathogenic in some tissues while protective in others. Any IL-24-targeted intervention strategy must therefore account for tissue context, receptor expression patterns and the possibility of off-target inflammatory effects. The authors also note that expression and purification of recombinant human IL-24 in Escherichia coli, together with polyethylene glycol site-specific modification, offers a route toward protein-based therapeutics, but delivery, immunogenicity and pharmacokinetics remain unsolved engineering problems.

What emerges from this synthesis is a cytokine with genuinely dual identity: a secreted tumor suppressor that kills malignant hepatocytes and reshapes antitumor immunity, and an intracellular guardian that protects hepatocytes from endoplasmic reticulum stress, restrains stellate cell activation and restores autophagic lipid clearance. The assembled molecular signaling map of IL-24, a resource designed to decipher its multifunctional immunoregulatory role in pathophysiological conditions, now provides researchers with a systematic framework for exploring these mechanisms. As the authors of the review conclude, the transition of IL-24 from bystander to key player in liver diseases is well supported by mechanistic data, but the leap from mouse models to IL-24-targeted intervention strategies in patients will require rigorous future investigation, better disease models and careful attention to the cytokine’s context-dependent behavior. For a molecule first discovered in melanoma cells thirty years ago, the liver may prove to be its most consequential arena yet.

Subject of Research: Interleukin-24 mechanisms and therapeutic potential in liver diseases

Article Title: From bystander to key player: The mechanisms and therapeutic potential of IL-24 in liver diseases

Article References: Cui, J., Chen, Y., Sun, C., & Nan, Y. (2026). From bystander to key player: The mechanisms and therapeutic potential of IL-24 in liver diseases. Molecular Biology Reports, 53(1), Article 1739. https://doi.org/10.1007/s11033-026-12941-1

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12941-1

Keywords: IL-24, liver disease, hepatocellular carcinoma, liver fibrosis, MASLD, cytokine, oncolytic virotherapy, ER stress, bystander, player, mechanisms, therapeutic