Hepatic stellate cells are the quiet custodians of the healthy liver. In their quiescent state, they store vitamin A droplets and maintain the extracellular matrix that provides structural support to the organ. When the liver is injured, however, these cells undergo a dramatic transformation. They lose their lipid droplets, proliferate, migrate to sites of damage, and begin producing massive quantities of collagen and other matrix proteins that accumulate as scar tissue. This activation process is metabolically expensive, and activated stellate cells, much like cancer cells, shift their energy production toward aerobic glycolysis, a phenomenon in which glucose is preferentially converted to lactate even in the presence of oxygen. This metabolic rewiring, sometimes called a Warburg-like shift, supplies the biosynthetic intermediates that rapidly dividing, matrix-producing cells need, but the upstream signals that coordinate this shift during stellate cell activation have remained poorly defined.

The Shanghai-led team set out to find those upstream signals, and their search converged on PRPF19, a ubiquitin ligase best known for its role in pre-mRNA splicing and DNA damage responses. The researchers found that PRPF19 expression was elevated in both human and mouse fibrotic livers, and that within these tissues the protein was enriched specifically in activated hepatic stellate cells. Crucially, the abundance of PRPF19 correlated positively with the severity of fibrosis, suggesting that the protein tracks with disease progression rather than being an incidental byproduct of liver injury. This clinical correlation provided the initial impetus to test whether PRPF19 was merely a marker of scarring or an active participant in the fibrogenic process.

To distinguish between these possibilities, the team turned to conditional genetic mouse models, an approach that allows a gene to be deleted in a specific cell type while leaving it intact elsewhere. Using mice carrying floxed Prpf19 alleles crossed with a tamoxifen-inducible Lrat-CreERT2 driver, they deleted the gene selectively in hepatic stellate cells. The result was striking: loss of Prpf19 in stellate cells attenuated both the activation of these cells and the development of liver fibrosis in vivo. In contrast, deleting Prpf19 in hepatocytes, the metabolic workhorses of the liver, using an Alb-CreERT2 driver produced no such protective effect. This cell-type specificity is a central finding of the study, because it demonstrates that PRPF19 acts within the stellate cells themselves rather than indirectly through neighboring parenchymal cells, and it positions the protein as a genuine driver of the fibrogenic response rather than a passive companion of injury.

With a causal role established, the researchers next asked what PRPF19 was actually doing inside the cells. They deployed an integrated multi-omics strategy, combining transcriptomic profiling of gene expression, proteomic analysis of the cellular protein complement, and metabolomic measurement of small-molecule metabolites. The convergence of these three data streams pointed in a single direction: PRPF19 sustains glycolytic flux, the rate at which glucose is funneled through the glycolytic pathway, and maintains the transcriptional programs that characterize activated stellate cells. When PRPF19 was absent, the cells’ metabolic engine downshifted, and the gene expression signature of activation faded. The metabolomic data in particular indicated that glycolytic intermediates and lactate production depended on PRPF19 levels, tying the protein directly to the energetic state of the cell.

The mechanistic heart of the paper concerns pyruvate kinase M2, or PKM2, the enzyme that catalyzes the final, rate-limiting step of glycolysis by converting phosphoenolpyruvate to pyruvate. PKM2 is famous in cancer biology for its ability to switch between an active tetrameric form in the cytoplasm and a monomeric or dimeric form that can translocate into the nucleus, where it acts as a transcriptional coactivator. The new study shows that PRPF19 promotes a specific chemical modification of PKM2: K63-linked ubiquitination, a form of the ubiquitin tag that, unlike the K48-linked version that condemns proteins to destruction, typically alters a protein’s behavior, localization, or interactions without marking it for degradation. In this case, K63-linked ubiquitination of PKM2 facilitated its movement into the nucleus of the stellate cell.

Once in the nucleus, ubiquitinated PKM2 does something consequential: it partners with hypoxia-inducible factor 1α, or HIF-1α, the master transcription factor that orchestrates cellular responses to low oxygen and drives glycolytic gene expression. The study demonstrates that nuclear PKM2 supports HIF-1α-dependent transcription of both glycolytic genes and fibrogenic genes, creating a feed-forward loop in which the metabolic enzyme and the transcription factor jointly enforce the activated stellate cell phenotype. In other words, PRPF19 sits at the top of a signaling cascade that converts a post-translational modification, the ubiquitin tag on PKM2, into a metabolic shift toward glycolysis and, simultaneously, into the transcriptional activation of collagen production and other fibrogenic outputs. This integration of post-translational signaling with metabolic reprogramming is precisely the kind of upstream regulatory mechanism that the field had been missing.

The significance of this work extends beyond the mechanics of a single protein pair. For decades, antifibrotic drug development has struggled because activated stellate cells are resilient, and broad approaches to suppress scarring have often produced unacceptable side effects. The PRPF19-PKM2 axis offers a more precise target: a pathway that is enriched in activated stellate cells, that is dispensable in hepatocytes at least with respect to fibrosis, and that sits upstream of both the metabolic and transcriptional hallmarks of activation. The cell-type-specific conditional knockout data suggest that interventions aimed at this pathway could, in principle, dampen stellate cell activation without broadly disrupting liver metabolism, although the authors’ findings in mice are early-stage and therapeutic translation would require substantial additional work, including the development of tools to modulate PRPF19 or its ubiquitination of PKM2 in a controlled way.

It is also worth noting what the study does not yet establish. The published work, which was released as a citable accepted manuscript under Springer Nature’s open access policy, reports findings from human tissue correlations and murine genetic models, and the authors, who include Guang-Cong Zhang, Shuang-Feng Zi, Baokui Ye, and Yi-Fan Ma as co-first contributors, declare no competing interests. Whether pharmacological inhibition of the PRPF19-PKM2-HIF-1α circuit can reverse established fibrosis in larger animal models, and whether PRPF19 levels in patient biopsies could serve as a predictive biomarker of disease trajectory, remain open questions for future research. Still, the study adds a compelling new node to the growing map of immunometabolism and fibrosis biology, illustrating how a splicing-associated ubiquitin ligase can moonlight as a metabolic regulator, and how the chemistry of a single ubiquitin linkage can ripple outward to reshape the fate of an entire organ.

Subject of Research: The role of PRPF19-mediated PKM2 ubiquitination in hepatic stellate cell activation and liver fibrosis

Article Title: PRPF19 drives hepatic stellate cell activation and liver fibrosis via PKM2-mediated glycolytic reprogramming

Article References: Zhang, G.-C., Zi, S.-F., Ye, B., Ma, Y.-F., Chen, J., Zhu, J.-M., Liu, T., Yin, J., Shen, X., Yu, X.-N., & Dong, L. (2026). PRPF19 drives hepatic stellate cell activation and liver fibrosis via PKM2-mediated glycolytic reprogramming. Nature Communications. https://doi.org/10.1038/s41467-026-78341-y

Image Credits: AI Generated

DOI: 10.1038/s41467-026-78341-y

Keywords: liver fibrosis, hepatic stellate cells, PRPF19, PKM2, glycolysis, HIF-1α, ubiquitination, metabolic reprogramming, K63-linked ubiquitin, liver disease, fibrogenesis, Nature Communications