The central player in the study is SOX9, short for SRY-box transcription factor 9. Transcription factors are proteins that bind to specific DNA sequences and control whether nearby genes are read into messenger RNA, and SOX9 is well known for its roles in embryonic development and tissue stem cell maintenance. In cancer, SOX9 has previously been implicated in tumor growth and progression, but its involvement in the metabolic transformation of metastatic colorectal cancer cells had remained largely unexplored. The new work positions SOX9 as a direct regulator of de novo lipogenesis, the process by which cells manufacture fatty acids from scratch rather than importing them from the bloodstream.

To dissect this relationship, the researchers combined several complementary approaches. They performed integrated transcriptomic and targeted lipidomic analyses, comparing the gene expression profiles and lipid compositions of cells with and without elevated SOX9. The transcriptomic data revealed changes in the expression of genes involved in fatty acid synthesis, while the lipidomic measurements showed that SOX9 overexpression increased the abundance of fatty acids and other lipid species within the cells. This convergence of genomic and metabolomic evidence provided the first indication that SOX9 overexpression drives fatty acid synthesis and lipid accumulation in colorectal cancer cells.

The team then verified these findings using an arsenal of imaging and analytical techniques. Nile Red staining, a fluorescent dye that preferentially labels neutral lipids, revealed increased lipid content in SOX9-overexpressing cells. Flow cytometry allowed the researchers to quantify lipid accumulation across large cell populations, confirming that the effect was consistent rather than confined to a few cells. Transmission electron microscopy provided ultrastructural evidence, visualizing the intracellular lipid deposits at nanometer resolution. Finally, Nanolive label-free lipid droplet imaging captured the dynamics of lipid storage structures inside living cells. Together, these methods demonstrated that SOX9 overexpression dramatically enhances intracellular lipid deposition, effectively transforming colorectal cancer cells into lipid-storing factories.

The clinical relevance of these observations became apparent when the researchers examined human tissue samples. SOX9 was found to be upregulated in colorectal cancer tissues compared with healthy tissue, and its expression was further enriched in metastatic lesions, the colonies of cancer cells that have established themselves in distant organs. Importantly, patients whose tumors showed high SOX9 levels had poorer outcomes, suggesting that the transcription factor is not merely a bystander in disease progression but a marker, and likely a driver, of aggressive disease.

Functional experiments cemented the link between SOX9-driven lipid production and metastatic behavior. In laboratory assays, cells with elevated SOX9 showed markedly increased migration and invasion, the two cellular behaviors that precede and enable metastatic spread. The team also performed lung metastatic colonization assays in animal models, which measure the ability of circulating cancer cells to seed and grow tumors in the lung. SOX9 overexpression promoted lung metastatic colonization, demonstrating that the lipid-reprogramming effect translates into real metastatic capacity in vivo.

Perhaps the most therapeutically significant result came from the rescue experiments. When the researchers inhibited fatty acid synthase, commonly abbreviated FASN, the enzyme that catalyzes the final steps of fatty acid synthesis, the pro-metastatic effects of SOX9 were significantly attenuated. Migration, invasion and lung colonization all declined when the fat-production line was shut down, even in cells still overexpressing SOX9. This result indicates that FASN sits downstream of SOX9 in the pathway and that the lipid synthesis it drives is not incidental but functionally required for SOX9 to promote metastasis. In principle, this makes the SOX9-FASN axis a metabolic vulnerability that could be targeted with drugs designed to starve metastatic cells of their lipid supply.

Mechanistically, the study went beyond correlation to show how SOX9 controls FASN in the first place. Using CUT&Tag sequencing, a technique that maps where a protein of interest binds across the genome, the researchers identified SOX9 occupancy at sites near the FASN promoter, the regulatory DNA region that controls how strongly the FASN gene is transcribed. This genomic binding evidence was complemented by luciferase reporter assays, in which the FASN promoter was fused to a light-producing reporter gene. When SOX9 was present, reporter activity increased, demonstrating that SOX9 can directly stimulate FASN promoter activity. Further reporter analyses using mutated promoter sequences supported a sequence-dependent mode of regulation, meaning SOX9 requires specific DNA motifs in the proximal FASN promoter to exert its effect, a hallmark of genuine direct transcriptional control rather than an indirect effect mediated through other genes.

The significance of this work lies in how it connects two major themes in modern cancer biology: transcriptional dysregulation and metabolic reprogramming. Cancer cells are known to rewire their metabolism to support rapid growth, survival under stress and dissemination, and increased lipid synthesis has emerged as a recurring feature of aggressive tumors. Lipids are not merely building blocks for new membranes in dividing cells; they also serve as signaling molecules, energy reserves and components of the machinery cells use to change shape and move through tissue. By showing that a developmental transcription factor can impose a lipogenic program on colorectal cancer cells and that this program is required for metastatic colonization, the study offers a coherent explanation for how metabolic flexibility and metastatic competence are coupled at the level of gene regulation.

The findings also suggest practical directions for future research and treatment development. Because FASN inhibition can rescue the metastatic phenotypes induced by SOX9, drugs targeting fatty acid synthase, some of which have already entered clinical evaluation for other cancers, could potentially benefit colorectal cancer patients whose tumors show high SOX9 expression. SOX9 itself, as a transcription factor, has historically been considered a difficult drug target, but its downstream metabolic dependencies offer an alternative point of attack. The study also raises the possibility that SOX9 expression levels could serve as a biomarker to identify patients at high risk of metastasis who might be candidates for metabolic therapies. As with all preclinical research, the results will need to be validated in larger clinical cohorts and tested in appropriately designed trials before they change patient care, but the identification of a defined SOX9-FASN lipid metabolic axis gives researchers a concrete molecular handle on one of the deadliest phases of colorectal cancer.

Subject of Research: SOX9-mediated regulation of lipid metabolism and metastasis in colorectal cancer

Article Title: SOX9 reprograms lipid metabolism via FASN to promote metastasis in colorectal cancer

Article References: Wang, H., Wei, L., Xiang, X., Li, J., Wang, Y., Jiang, Z., Li, X., Li, Y., Pan, Y., & Liang, X. (2026). SOX9 reprograms lipid metabolism via FASN to promote metastasis in colorectal cancer. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-09055-4

Image Credits: AI Generated

DOI: 10.1186/s12967-026-09055-4

Keywords: colorectal cancer, SOX9, FASN, lipid metabolism, metastasis, fatty acid synthesis, de novo lipogenesis, transcription factors, cancer metabolism, CUT&Tag, lung metastasis, Journal of Translational Medicine

The modification in question is lysine succinylation, a post-translational change in which a succinyl group is chemically attached to a lysine amino acid residue on a protein. Lysine succinylation is known to influence metabolism and transcription in a range of organisms, and previous work had charted its behavior during rice development. What remained largely unexplored was whether this modification plays a role in biotic stress — the umbrella term for damage inflicted on plants by living attackers such as viruses, bacteria, and insects. The new research, led by Lei Yang and Shuai Li together with colleagues at Yangzhou University, the Jiangsu Academy of Agricultural Sciences, and Anhui Normal University, demonstrates that it does, and in strikingly consequential ways.

To probe the question, the team performed quantitative succinylome profiling, a mass-spectrometry-based survey that measures lysine succinylation across thousands of proteins simultaneously. They applied the technique to rice plants subjected to viral infection and to herbivore infestation, and the results revealed extensive, stress-responsive succinylation on both histone and non-histone proteins. The modification preferentially decorated highly abundant proteins and was concentrated in pathways tied to photosynthesis and core metabolism. Notably, the data showed that herbivore attack increased lysine succinylation while suppressing the expression of photosynthetic pathway-related proteins, hinting that the modification tracks the metabolic reorganization plants undergo when under attack.

A central technical achievement of the study was the application of CUT&Tag analysis — a genome-mapping method that pinpoints where a particular histone modification sits along the chromosomes — to lysine succinylation in rice. The mapping showed strong enrichment of the mark at the promoters of defense-related genes, particularly genes involved in plant hormone signal transduction. Crucially, the researchers found a positive correlation between lysine succinylation occupancy at these regulatory regions and the expression levels of the corresponding genes. In other words, when the succinyl mark was present at a gene’s promoter, that gene was more likely to be actively transcribed. This positions lysine succinylation not as a passive byproduct of cellular chemistry but as an active participant in defense-related transcriptional control.

Because a modification’s abundance reflects a balance between the enzymes that add it and those that remove it, the team went hunting for desuccinylases — enzymes that strip succinyl groups from lysine residues. Working in rice, they identified three histone deacetylases as major desuccinylases: OsSRT702, OsHDA714, and OsHDA716. The researchers purified an OsHDA714-His fusion protein and validated its desuccinylation activity in vitro, confirming that the enzyme could directly remove the mark. They also generated CRISPR/Cas9-mediated knockout mutations in the corresponding genes and verified the edits by DNA sequencing, providing a clean genetic system in which to test the enzymes’ biological roles.

The functional results were dramatic. Disrupting OsHDA714 markedly enhanced rice resistance to rice stripe virus and rice black-streaked dwarf virus, two important viral pathogens of the crop, and also to the brown planthopper and the striped stem borer, two of the most destructive insect pests in rice-growing regions. A single gene knockout thus broadened resistance across two viral and two insect attackers, a breadth that conventional single-resistance breeding rarely achieves. This pattern suggests that OsHDA714 normally functions as a negative regulator of immunity — a brake on the plant’s defensive responses — and that releasing the brake, by removing the enzyme, activates a wider defense program.

To understand what that defense program consists of, the researchers integrated transcriptomic data with their CUT&Tag maps. Genes upregulated in the hda714 knockout mutant turned out to be predominantly enriched in the phenylpropanoid biosynthesis pathway, a metabolic route that produces an arsenal of antimicrobial and anti-herbivore compounds, and many of these genes carried lysine succinylation marks in their promoter regions. In parallel, jasmonate-associated defense pathways were activated in the mutant. Jasmonates are plant hormones best known for orchestrating responses to wounding and herbivory, and their involvement links the epigenetic machinery of succinylation directly to classical hormonal defense signaling. Phytohormone measurements in the mutant and in wild-type ZH11 plants supported this remodeling of hormone pathways.

Taken together, the results sketch a coherent mechanistic model. Under normal conditions, OsHDA714 — aided by OsSRT702 and OsHDA716 — keeps lysine succinylation levels in check, limiting succinyl marks at defense gene promoters and thereby restraining the expression of hormone-signaling and phenylpropanoid genes. When viruses or herbivores attack, this regulation is perturbed, succinylation accumulates on histones and key metabolic proteins, and defense transcription is reprogrammed. Removing OsHDA714 genetically locks the system into a primed state, in which the plant constitutively deploys the biochemical tools needed to fend off a diverse range of attackers. The authors propose that OsHDA714-mediated desuccinylation modulates hormone signaling and phenylpropanoid metabolism to control broad-spectrum resistance in rice.

The study carries practical implications for crop protection. Rather than stacking individual resistance genes against specific pathogens — a strategy that pathogens and pests frequently circumvent — agricultural scientists could target a regulatory hub like OsHDA714 to bolster multiple defenses simultaneously. Because the work was performed with genome editing tools such as CRISPR/Cas9, the pathway from discovery to improved germplasm is conceptually straightforward, although field performance, agronomic trade-offs, and potential effects on growth and yield would need careful evaluation, since defense activation often competes with productivity. More broadly, the research expands the known repertoire of histone modifications that regulate plant immunity, positioning lysine succinylation alongside better-characterized marks such as acetylation and methylation as a genuine epigenetic regulator of defense. It also raises questions for future work: how the cell senses viral or herbivore attack and translates it into altered succinylation, what non-histone succinylated proteins contribute to the response, and whether parallel systems operate in other crops. For now, the study provides the clearest evidence yet that a chemical tag on rice histones sits at the heart of the plant’s ability to defend itself against some of agriculture’s most persistent enemies.

Subject of Research: Role of lysine succinylation in rice defense responses against viral pathogens and herbivorous insects

Article Title: Lysine succinylation mediates defense responses against viruses and herbivores in rice

Article References: Yang, L., Li, S., Deng, X., Zhao, R., Meng, Y., Li, C., Qin, L., Liu, B., Sun, Y., Fang, J., Ji, R., & He, Z. (2026). Lysine succinylation mediates defense responses against viruses and herbivores in rice. Genome Biology. https://doi.org/10.1186/s13059-026-04271-z

Image Credits: AI Generated

DOI: 10.1186/s13059-026-04271-z

Keywords: rice, lysine succinylation, histone modification, OsHDA714, plant immunity, rice stripe virus, brown planthopper, jasmonate signaling, phenylpropanoid biosynthesis, CUT&Tag, CRISPR/Cas9, epigenomics