Uncoupling Metabolic Reprogramming in Hepatocellular Carcinoma: The JOSD1-PGAM1 Ubiquitination-Lactylation Switch

Highlights

• JOSD1 is identified as a critical deubiquitinase overexpressed in hepatocellular carcinoma (HCC) that correlates with poor clinical outcomes.
• The JOSD1-AARS1 axis regulates a specific ‘ubiquitination-lactylation’ crosstalk at the K251 residue of the glycolytic enzyme PGAM1.
• Elevated JOSD1 stabilizes PGAM1 and enhances its enzymatic activity, leading to massive lactate accumulation and CD8+ T cell exhaustion.
• Targeting JOSD1 via liver-specific delivery systems synergizes with anti-PD-1 therapy to overcome immune resistance in HCC models.

Background

Hepatocellular carcinoma (HCC) remains a global health challenge, characterized by high recurrence rates and limited therapeutic options for advanced-stage patients. A defining feature of HCC is metabolic reprogramming, primarily the ‘Warburg effect,’ where cancer cells prioritize glycolysis over oxidative phosphorylation even in the presence of oxygen. This metabolic shift not only fuels rapid proliferation but also alters the tumor microenvironment (TME) through the accumulation of metabolic byproducts like lactate.

Recent advances in molecular biology have highlighted the importance of post-translational modifications (PTMs) in regulating metabolic enzymes. While ubiquitination and phosphorylation are well-studied, newer modifications like lysine lactylation (Kla) have emerged as pivotal links between cellular metabolism and protein function. However, the precise mechanisms governing the crosstalk between different PTMs—specifically how deubiquitinases might influence non-proteolytic modifications like lactylation—have remained largely enigmatic until the identification of the JOSD1-AARS1-PGAM1 axis.

Key Content

Identification of JOSD1 as a Glycolytic Driver in HCC

Integrating multi-omics data from patient cohorts and HCC cell lines, researchers identified Josephine Domain-Containing 1 (JOSD1) as a significantly upregulated gene in malignant liver tissues. High expression of JOSD1 is not merely a marker but a functional driver of the disease; its overexpression is statistically correlated with advanced TNM staging, shorter overall survival, and a distinct glycolytic gene expression signature. In vitro assays demonstrated that JOSD1 knockdown significantly reduces glucose consumption and lactate production, effectively slowing down the ‘metabolic engine’ of the HCC cell.

Mechanistic Insight: The Ubiquitination-Lactylation Switch

The core of JOSD1’s oncogenic function lies in its interaction with Phosphoglycerate Mutase 1 (PGAM1), a key enzyme in the glycolytic pathway that converts 3-phosphoglycerate to 2-phosphoglycerate. The study elucidated a sophisticated regulatory mechanism involving the JOSD1-AARS1 axis:

• The K251 Residue: The lysine residue at position 251 (K251) of PGAM1 serves as a competitive site for different PTMs. Under normal physiological conditions, K251 is susceptible to ubiquitination, which marks PGAM1 for proteasomal degradation.
• The Deubiquitinase Function: JOSD1 acts as a deubiquitinase that removes these ubiquitin chains from PGAM1, preventing its degradation and increasing its protein stability.
• The Lactylation Synergy: Once stabilized by JOSD1, PGAM1 becomes a substrate for AARS1 (Alanyl-tRNA Synthetase 1), which facilitates its lactylation at the same K251 site. This lactylation further boosts the enzymatic activity of PGAM1, creating a feed-forward loop that accelerates glycolytic flux.

Metabolic Suppression of the Immune Response

One of the most clinically relevant findings of this research is the link between JOSD1-driven metabolism and immune evasion. The heightened activity of PGAM1 leads to excessive extracellular lactate. High lactate concentrations in the TME have been shown to inhibit the infiltration and cytotoxic function of CD8+ T cells. By measuring immune cell profiles in HCC tissues, the researchers found that high JOSD1 levels inversely correlate with the density of functional CD8+ T cells, suggesting that JOSD1-mediated metabolic reprogramming creates an ‘immune cold’ environment.

Therapeutic Potential and Synergy with Anti-PD-1

The study explored the translational potential of JOSD1 inhibition. Using liver-targeted delivery systems (such as nanoparticle-encapsulated siRNAs or small molecule inhibitors), the researchers observed a marked reduction in tumor volume in orthotopic HCC mouse models. More importantly, when combined with anti-PD-1 antibodies, JOSD1 inhibition sensitized the tumors to immunotherapy. The reduction in lactate levels following JOSD1 blockade ‘re-warmed’ the TME, allowing for restored T cell activity and prolonged survival in animal models that were previously resistant to checkpoint inhibitors.

Expert Commentary

The discovery of the JOSD1-AARS1-PGAM1 axis represents a significant leap in our understanding of ‘PTM crosstalk.’ For years, researchers viewed ubiquitination primarily as a ‘death tag’ for proteins. This study demonstrates that deubiquitinases like JOSD1 do more than just prevent degradation; they can act as molecular switches that prepare a protein for other activating modifications like lactylation. From a clinical perspective, this provides a dual-strike opportunity: by targeting JOSD1, we can simultaneously cripple the tumor’s energy supply and dismantle its immune-shielding lactate barrier.

However, several challenges remain. The specificity of JOSD1 inhibitors must be rigorously tested to avoid off-target effects in healthy liver tissue or other organs. Furthermore, while the mouse models are promising, the heterogeneity of human HCC metabolism means that JOSD1 might be a primary driver in only a specific subset of patients. Biomarker-driven patient selection will likely be necessary for future clinical trials.

Conclusion

JOSD1 is a critical upstream regulator of metabolic reprogramming in HCC, operating through a novel ubiquitination-lactylation switch on PGAM1. This mechanism not only promotes tumor growth but also facilitates immune evasion by altering the metabolic landscape of the TME. Targeting JOSD1, particularly in combination with modern immunotherapies like anti-PD-1, offers a potent therapeutic strategy to improve outcomes for patients with aggressive, glycolytic HCC. Future research should focus on refining JOSD1 inhibitors and validating K251 lactylation as a predictive biomarker for treatment response.

References

• Li Q, et al. JOSD1 drives hepatocellular carcinoma malignancy by modulating the ubiquitination-lactylation switch on PGAM1. Gut. 2026-04-28. PMID: 42049490.
• Zhang D, et al. Metabolic regulation of gene expression by histone lactylation. Nature. 2019;574(7779):575-580.
• Heiden MGV, et al. Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation. Science. 2009;324(5930):1029-1033.