A team led by Shijin Wang, Yubin Tang, and colleagues, writing in PLOS Pathogens, now reports a molecule that may change that picture. The researchers describe RMP(R8), an engineered peptide that mimics the part of a human protein called SCARB2, which the viruses use as their essential gateway into cells. In laboratory tests the compound blocked EV-A71 and CV-A16 at remarkably low concentrations, showed an excellent safety profile, and improved survival in a lethal neonatal mouse model of infection. The work also resolves a paradox that has frustrated antiviral developers for roughly a decade, and in doing so proposes a new playbook for drugging virus-receptor interactions that occur deep inside cells rather than on their surfaces.

To appreciate why the finding matters, it helps to understand how these viruses gain entry. EV-A71 and CV-A16 belong to the genus Enterovirus within the family Picornaviridae, small non-enveloped viruses whose outer shell is built from four structural proteins arranged with icosahedral symmetry. For enteroviruses of this group, attachment to a surface receptor is only the first act. The truly decisive step, known as uncoating, occurs after the virus has been taken up into the cell, when the protein shell rearranges or releases its RNA genome so replication can begin. SCARB2, a lysosomal membrane protein found abundantly on many human cell types, is the receptor that triggers this uncoating reaction. Structural studies have shown that binding of the virion to SCARB2 destabilizes the capsid, converting the virus into an expanded particle that expels its genome into the cytosol.

That mechanism suggests an obvious therapeutic strategy, at least on paper. If a soluble fragment of SCARB2 floating outside the cell could latch onto incoming virus particles and prematurely trip their uncoating switch, the virus would fall apart harmlessly in extracellular fluid. Such receptor decoys have succeeded against other pathogens, and researchers duly built Fc-fusion proteins carrying the extracellular domain of SCARB2. The results were consistently disappointing. The decoys failed to neutralize EV-A71 in meaningful ways, a puzzle that has stood in the literature for some ten years and discouraged further investment in SCARB2-based antivirals. The reason, as the new study makes clear, is that SCARB2 does its critical work not on the cell surface but inside the endosomal and lysosomal compartments, where the acidity and protease environment differ dramatically from conditions outside the cell and where a large, bulky Fc-fusion protein simply cannot follow the virus.

The team’s solution was to shrink the receptor to its functional core and smuggle it to where it is needed. Mining the structure of the SCARB2-virion interface, they identified a short stretch of the protein, spanning amino acids W146 through K166, as the minimal region that binds VP2, one of the capsid proteins on the viral shell. They fused this twenty-one-residue binding domain to octa-arginine, a classical cell-penetrating peptide composed of eight positively charged arginine residues. The result is RMP(R8), an intracellular receptor mimetic: small enough to cross cell membranes and enter the cytosol and vesicular compartments, yet retaining the binding surface that the virus itself recognizes. In effect, the molecule impersonates the receptor inside the cell, contacting virus particles at the very stage where extracellular decoys are absent and where premature engagement spells disaster for the pathogen.

The numbers reported for the compound are striking. RMP(R8) inhibited EV-A71 with a half-maximal effective concentration of 0.156 micrograms per milliliter, a potent value for a peptide antiviral. Its selectivity index, the ratio comparing the dose that harms host cells with the dose that blocks the virus, exceeded 2003, indicating a wide therapeutic margin. The peptide also dissolved readily in water, an unglamorous but decisive property for any molecule hoping to be formulated, dosed, and distributed clinically. In cultured cells derived from the intestine and the nervous system, tissues that matter most for enterovirus disease, RMP(R8) suppressed infection by genetically divergent EV-A71 isolates as well as by CV-A16, suggesting the activity is not confined to a single laboratory strain but extends across the viral diversity that vaccines and strain-specific antibodies struggle to cover.

Mechanistically, the authors traced the compound’s action to the blockage of viral entry. Rather than preventing attachment to the cell surface, RMP(R8) interferes with the intracellular step at which SCARB2 normally catalyzes uncoating. By engaging the virion’s VP2-binding site at the wrong time and place, the mimetic presumably triggers or locks the capsid into a state that cannot deliver its genome productively. This timing explains the failure of the older decoys and the success of the new one: the virus is vulnerable to receptor mimicry only after it has entered the cell, and only a molecule that reaches that compartment can exploit the vulnerability. The concept is generalizable in principle. Any virus that performs its key receptor-dependent step intracellularly, and there are several among the picornaviruses and related families, could in theory be targeted by a cell-penetrating mimetic of the relevant receptor domain.

Animal testing provided the strongest evidence that the approach survives contact with a living system. In a lethal neonatal mouse model, the standard challenge assay for EV-A71 pathogenesis, treatment with RMP(R8) significantly increased survival of infected pups following challenge with EV-A71 and with CV-A16 alike. Neonatal mice lack a mature immune system and are exquisitely susceptible to these viruses, so a survival benefit in this setting is a meaningful benchmark for a candidate antiviral. The breadth across two distinct viral species is particularly notable, because cross-species coverage is rare among antivirals that target viral enzymes or capsid pockets, which are easily undermined by a handful of point mutations. Targeting the conserved receptor-binding surface, by contrast, raises the genetic barrier to escape.

Considerable work remains between a promising peptide and an approved medicine. RMP(R8) must still demonstrate an acceptable pharmacokinetic profile, stability against proteases, appropriate tissue distribution, and safety in larger animals, and the dosing window in human infection, where treatment would likely begin after symptom onset, will need careful definition. Cell-penetrating peptides also face well-known questions about delivery and clearance in patients. Even so, the study stands out for solving a concrete mechanistic puzzle: it explains why extracellular SCARB2 decoys failed, and it converts that explanation into a working drug candidate with potency, breadth, and in vivo efficacy. For the millions of children at risk of severe hand, foot, and mouth disease each year, and for the clinicians who currently have nothing specific to offer them, an intracellular receptor mimetic that attacks EV-A71 and CV-A16 at their most vulnerable moment represents exactly the kind of targeted therapy the field has been waiting for. It also redraws the boundary of antiviral design, showing that the inside of the cell, long considered hostile territory for receptor-based drugs, can be reached and exploited.

Subject of Research: Intracellular SCARB2 receptor mimicry as a broad antiviral strategy against enteroviruses causing hand, foot, and mouth disease

Article Title: Intracellular SCARB2 mimicry overcomes decoy failure to broadly inhibit enteroviruses

Article References: Wang, S., Tang, Y., Lai, S., Yang, J., Yang, Q., Liu, X., Yu, X.-F., Guo, H., & Wei, W. (2026). Intracellular SCARB2 mimicry overcomes decoy failure to broadly inhibit enteroviruses. PLOS Pathogens, 22(10), e1014699. https://doi.org/10.1371/journal.ppat.1014699

Image Credits: AI Generated

DOI: 10.1371/journal.ppat.1014699

Keywords: EV-A71, coxsackievirus A16, enterovirus, SCARB2, hand foot and mouth disease, antiviral peptide, receptor mimicry, viral uncoating, cell-penetrating peptide, PLOS Pathogens, neonatal mouse model, viral entry

Lactylation first attracted wide attention as a modification of histones, the proteins around which DNA is wound, where it was shown to activate gene expression in response to metabolic cues. More recently, researchers have realized that lactylation also strikes non-histone proteins, potentially rewiring signaling pathways throughout the cell. The new study addresses a key gap in this emerging field: what lactylation actually does to non-histone proteins inside hepatocellular carcinoma, and whether those effects matter for patients. The answer, according to the team, is that lactylation can functionally reprogram a tumor suppressor, converting a molecular brake on cancer into a bystander that no longer applies the brakes effectively.

OVOL2, short for Ovo-like zinc finger 2, is a transcription factor, a DNA-binding protein that controls the activity of target genes. In the liver, it has been associated with restraining epithelial-mesenchymal transition, the cellular program that allows stationary epithelial cells to become invasive and migratory, a hallmark of cancer progression. The researchers began by mining large public datasets from The Cancer Genome Atlas and the Gene Expression Omnibus, and found that OVOL2 messenger RNA is consistently reduced in hepatocellular carcinoma tissues compared with healthy liver tissue. That observation fit the conventional view of OVOL2 as a gene that cancer cells would prefer to silence.

But when the team examined human hepatocellular carcinoma samples and paired adjacent non-tumorous tissues directly, they noticed something paradoxical. Signals associated with OVOL2 lactylation were elevated in the tumor tissues, and higher levels of these lactylation marks correlated with shorter overall survival and increased postoperative recurrence. Notably, however, in multivariate analysis that accounted for other clinical variables, OVOL2 lactylation was not an independent prognostic factor, an important caveat the authors report transparently. The correlation suggests the modification tracks with aggressive disease, even if it does not stand alone as a predictive marker once standard clinical parameters are considered.

To characterize the modification at the molecular level, the researchers deployed a demanding toolkit: immunoprecipitation to pull OVOL2 out of cell extracts, immunoblotting and immunofluorescence to detect and localize the modified protein, immunohistochemistry to map its distribution in tissue sections, and liquid chromatography coupled with tandem mass spectrometry to pinpoint exactly where on the protein the lactyl group lands. The mass spectrometry identified lysine 3, the third amino acid in the OVOL2 protein, as the site of modification. Lysine residues carry positively charged side chains that often participate in critical molecular interactions, so adding a bulky, chemically distinct lactyl group at such a position can profoundly change how a protein behaves.

The enzyme responsible for installing the mark turned out to be KAT8, a lysine acetyltransferase better known for modifying histones. When the team manipulated KAT8 levels, OVOL2 lactylation rose and fell accordingly, establishing KAT8 as the writer of this particular mark. The functional consequences were dramatic. Lactylation at lysine 3 reduced the ability of OVOL2 to accumulate in the nucleus, the compartment where a transcription factor must reside to do its job. Subcellular fractionation experiments confirmed this shift, and the weakened nuclear presence translated into a loss of transcriptional repression at one of OVOL2’s key target genes, TRIM54, which encodes tripartite motif-containing 54, an E3 ubiquitin ligase that tags other proteins for destruction.

With OVOL2’s grip on TRIM54 loosened, TRIM54 levels climbed, and the consequences cascaded further down the chain. The study shows that elevated TRIM54 promotes K48-linked ubiquitination of RBM47, an RNA-binding protein whose abbreviation stands for RNA-binding motif 47. K48-linked ubiquitin chains are the canonical signal that directs a protein to the proteasome, the cell’s garbage disposal complex, for degradation. In other words, the pathway reads like a molecular relay: lactate accumulation leads to KAT8-mediated lactylation of OVOL2 at lysine 3, which weakens the tumor suppressor’s nuclear function, which lifts repression of TRIM54, which destroys RBM47, and which ultimately facilitates hepatocellular carcinoma growth. Each link in that chain was tested with gain- and loss-of-function assays, reporter assays, chromatin immunoprecipitation and CUT&Tag, a technique called cleavage under targets and tagmentation that maps where a protein binds across the genome.

Perhaps the most clinically provocative part of the study is the therapeutic proof of concept. The researchers designed a cell-penetrating peptide, a short amino acid chain that can cross cellular membranes, aimed at reducing OVOL2 lactylation. When evaluated in cell line-derived xenograft models, in which human cancer cells are implanted into animals, the peptide suppressed tumor growth in vivo. The result suggests that blocking a single lactylation event on a single protein may be enough to restore some tumor-suppressive function, offering a template for drugs that target the lactylation machinery rather than the metabolic pathway as a whole. Cell-penetrating peptides remain an early-stage modality, and the authors are careful to frame this as a potential strategy rather than a ready treatment, but the experiment demonstrates that the pathway is pharmacologically addressable.

The broader significance of the work lies in its reframing of what a tumor suppressor is. Textbook descriptions often treat these proteins as fixed entities whose loss, through mutation or deletion, removes a brake on cell division. This study instead highlights what the authors call post-translational modification-dependent functional plasticity: a tumor suppressor can be present and genetically intact yet functionally neutralized by a chemical tag imposed by the metabolic environment. In tumors such as hepatocellular carcinoma, which arise frequently in the context of metabolic disease and hypoxic, nutrient-stressed tissue, lactate is abundant, and the lactylation landscape is correspondingly rich. A suppressor like OVOL2 can thus be silenced without ever touching its gene.

For patients with hepatocellular carcinoma, one of the deadliest cancers worldwide and one whose incidence continues to climb in parallel with obesity, diabetes and viral hepatitis, the study offers both a mechanistic insight and a cautious note of realism. The clinical data link OVOL2 lactylation to survival and recurrence, but not independently of established prognostic factors, and the therapeutic peptide has so far been tested only in animal models. Still, the identification of a KAT8-OVOL2-TRIM54-RBM47 axis gives researchers a defined set of molecular targets, and it strengthens the case that the metabolic tumor microenvironment communicates with the genome not only through gene expression but through chemical edits to the proteins that read the genome itself. As lactylation research matures, tumors may increasingly be understood as ecosystems in which waste products become weapons, and the next generation of therapies may aim to disarm them at the point of attachment.

Subject of Research: Lactylation of the tumor suppressor OVOL2 in hepatocellular carcinoma progression

Article Title: Lactylation of OVOL2 impairs its tumor-suppressive activity to promote hepatocellular carcinoma growth

Article References: Zhang, Z., Chen, Z., Wu, J., Ye, D., Yao, Y., Wu, H., Zhang, X., Yang, H., Wang, X., & Tang, N. (2026). Lactylation of OVOL2 impairs its tumor-suppressive activity to promote hepatocellular carcinoma growth. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-08959-5

Image Credits: AI Generated

DOI: 10.1186/s12967-026-08959-5

Keywords: OVOL2, lactylation, hepatocellular carcinoma, KAT8, TRIM54, RBM47, post-translational modification, tumor suppressor, cancer metabolism, ubiquitination, liver cancer, cell-penetrating peptide