Hepatocellular carcinoma, or HCC, is the main form of primary liver cancer. It is common, deadly, and often found late, which is a lousy combo for everyone involved (Zheng et al., 2025); (Seyhan et al., 2025). One reason HCC is so hard to treat is that liver tumors do not just grow fast. They also remodel the whole neighborhood around them, including the immune cells that should be shutting the place down (Lin et al., 2024).
To understand this paper, you need two bits of background.
First, glycolysis is the cell’s quick-and-dirty way to turn glucose into usable energy. Cancer cells love it because it is fast and feeds growth, even if it is a bit nutritionally chaotic (Park and Hall, 2025). Second, proteins can be modified after they are made. Think of that as office sticky notes for the cell. Some notes say "keep this," some say "move this," and some basically say "throw this in the shredder."
One of those notes is ubiquitination, which often marks a protein for breakdown. Another is lactylation, a newer modification linked to lactate, the byproduct that piles up when glycolysis is running hot. Because of course cancer was not content with growing recklessly. It also had to become a part-time stationery expert.
JOSD1, Meet PGAM1. This Will End Badly.
The paper found that JOSD1 is elevated in HCC and linked with worse prognosis. When researchers boosted JOSD1, tumor cells became more aggressive and more glycolytic. When they blocked it, those malignant behaviors dropped (Li et al., 2025).
Mechanistically, the key target was PGAM1, a glycolysis enzyme. JOSD1, together with AARS1, controlled a switch on PGAM1 involving ubiquitination and lactylation at a specific site called K251. In plain English: JOSD1 helped prevent PGAM1 from being cleared away, while the lactylation side of the switch helped keep the enzyme stable and active. More stable PGAM1 meant more glycolysis. More glycolysis meant more lactate. More lactate meant the tumor microenvironment got even more hostile to immune attack.
It is a neat bit of biochemical irony. The tumor’s garbage-tag system and its sugar-burning habit are not separate stories. They are collaborating. Like two bad interns who somehow become extremely productive the moment the project turns evil.
Why This Matters for Immunotherapy
The most interesting part is not just that JOSD1 helps tumors grow. It is that this metabolic rewiring seems to blunt CD8 T-cell function and weaken response to anti-PD-1 immunotherapy (Li et al., 2025). That fits a broader pattern in liver cancer research: metabolism and immunity are constantly elbowing each other in the ribs (Lin et al., 2024); (Seyhan et al., 2025).
This is not just abstract molecular weirdness. Immunotherapy can help some HCC patients, but not nearly enough of them, and resistance remains a major problem (Zheng et al., 2025). If a tumor can use lactate-fueled chemistry to tire out the immune system before treatment even gets traction, that is a real obstacle, not just a cute pathway diagram.
The authors also report that liver-targeted inhibition of JOSD1 suppressed tumor progression and worked synergistically with anti-PD-1 therapy in preclinical models (Li et al., 2025). That is the sort of finding that makes oncologists lean forward slightly instead of maintaining the standard issue "interesting mouse data, call me when humans exist" face.
The Big Takeaway
This study suggests HCC is not merely addicted to glucose. It is using the fallout from that addiction to reprogram protein behavior and dodge immune destruction. JOSD1 appears to sit upstream of that whole mess, acting like a molecular switchboard operator for metabolism and immune evasion.
If these results hold up, JOSD1 could become a therapeutic target with a two-for-one appeal: slow the tumor’s metabolic engine and make immunotherapy less likely to arrive at a locked door. That is still a big "if." Biology has a long tradition of being promising right up until it meets a clinical trial. But this is exactly the kind of mechanistic insight that can turn vague hope into a smarter drug strategy.
And honestly, any paper that reveals a tumor has been moonlighting as both a metabolic hacker and an immune saboteur deserves a little attention.
References
Li Q, Yu K, Zhou S, et al. JOSD1 drives hepatocellular carcinoma malignancy by modulating the ubiquitination-lactylation switch on PGAM1. Gut. 2025. DOI: https://doi.org/10.1136/gutjnl-2025-337331
Park S, Hall MN. Metabolic reprogramming in hepatocellular carcinoma: mechanisms and therapeutic implications. Experimental & Molecular Medicine. 2025;57:515-523. DOI: https://doi.org/10.1038/s12276-025-01415-2
Lin J, Rao D, Zhang M, et al. Metabolic reprogramming in the tumor microenvironment of liver cancer. Journal of Hematology & Oncology. 2024;17:6. DOI: https://doi.org/10.1186/s13045-024-01527-8
Seyhan D, Allaire M, Fu Y, et al. Immune microenvironment in hepatocellular carcinoma: from pathogenesis to immunotherapy. Cellular & Molecular Immunology. 2025;22:1132-1158. DOI: https://www.nature.com/articles/s41423-025-01308-4
Zheng J, Wang S, Xia L, et al. Hepatocellular carcinoma: signaling pathways and therapeutic advances. Signal Transduction and Targeted Therapy. 2025;10:35. DOI: https://doi.org/10.1038/s41392-024-02075-w
Disclaimer: The image accompanying this article is for illustrative purposes only and does not depict actual experimental results, data, or biological mechanisms.