Cdc42’s emerging role in gut health and disease

What is CDC42's role in the gut?

Cdc42 is important for tissue and organ development, including in the gut. For example, Cdc42 was shown to regulate intestinal epithelial cell (IEC) migration, proliferation, and polarity, and studies in mice lacking Cdc42 specifically in intestinal epithelial cells displayed gross hyperplasia, abnormal epithelial permeability, and crypt enlargement⁸.

Another study suggests that Cdc42 may also be important for regulating gut function through controlling intestinal epithelial stem cell (IESC) homeostasis⁹. IESCs lacking Cdc42 led to defective polarity and hyperplasia of intestinal crypts¹⁰. A recent study by Zhang et al. supports the role of Cdc42 in controlling IESC progenitor function and found that loss of Cdc42 promoted mucosal inflammation while reducing IESC regeneration and IESC repair¹¹.

Intriguing work by the Ivanov group reported how Cdc42-dependent endocytic vesicles from IECs, which contain segmented filamentous bacterial (SFB) cell walls, can activate CD4 T cells and promote SFB-induced Th17 cell differentiation (see Figure 1)⁷. This study identified a unique crosstalk mechanism between commensal microbes and IECs to control immune cells during normal physiologic function.

In another study, Cho et al. found that structural variants in lipid A, which are found in gram-negative commensal microbes, can drastically alter the host’s immunological response in the gut¹². For example, they found that some lipid A structures induce sustained interferon-β responses, which were mediated by Cdc42-dependent TLR4 endocytosis to control gut inflammation. Clearly, Cdc42 signaling has a profound effect on gut homeostasis and may be a critical mechanism for controlling distinct communication mechanisms between host cells and commensal microbes in the gut.

Does Cdc42 contribute to inflammatory bowel disease?

IBD, which encompasses ulcerative colitis (UC) and Crohn’s disease, is characterized by progressive intestinal inflammation, which is caused by a combination of genetic, environmental, microbiota, and immune system dysfunction¹³. Importantly, several studies have shown that distinct microbiota can activate small GTPases like Cdc42 as part of their pathogenesis in IBD¹³.

As discussed above, Cdc42 plays a key role in controlling immune cell activation and inflammation in the gut, but it also contributes to chronic gut inflammation through other mechanisms as well. For instance, a study reported that depleted Cdc42 in IECs impairs differentiation, which led to a dysfunctional intestinal barrier that resulted in chronic inflammation in the gut⁸. Therefore, it is fair to wonder how Cdc42 dysfunction in the gut contributes to IBD.

In a study using mice bearing IBD, investigators found that Cdc42 regulated immune response and inflammation in the gut, and Cdc42 treatment could reduce inflammatory cytokines in colon tissue¹⁴. A supportive study by the Ma group found that Cdc42 levels were reduced in patients with UC compared to UC patients in remission, and that treatment with infliximab elevated Cdc42 levels¹⁵.

Conversely, another group found that the drug paeoniflorin was effective at ameliorating UC symptoms in a rat model through direct inhibition of Cdc42, which led to suppressed oxidative stress, inflammation, and apoptosis¹⁶.Yet, in another study using hyperglycemic rats with IBD, it was shown that elevated Cdc42 levels were found in the small and large intestines of these IBD rats, but surprisingly found reduced Cdc42 levels in their colon tissue¹⁷.

Collectively, these recent studies contribute to the existing body of knowledge that suggests Cdc42 dysregulation is involved in IBD; however, further investigation is needed to fully understand how, where, and when Cdc42 contributes to IBD progression.

Several studies looking for early biomarkers for gastric cancer also identified Cdc42 as a prominent marker⁴.For example, in a proteome profiling study of urine from patients with gastric lesions, Cdc42 was identified as one of four proteins linked to the progression of gastric mucosa lesions and gastric cancer progression²⁴.

Cdc42 overexpression acts as an oncogene in CRC and functions primarily through its ability to regulate cell migration and proliferation^19,25,26. A recent study showed that Cdc42 subcellular localization in response to VEGF/NRP1 may be important for directed migration, invasion, and metastasis in CRC²⁷. Remarkably, this pattern of subcellular Cdc42 predicted poor prognosis in CRC patients.

In gastric cancers, Cdc42 also contributes to disease progression through altering cell migration and proliferation^28,29. Collectively, there is strong evidence that Cdc42 contributes to gastrointestinal cancer progression.

Is there more to learn about Cdc42 in the gut?

The overall body of work describes a critical role for Cdc42 in the physiologic and pathologic function of the gastrointestinal system. While intriguing studies highlight Cdc42’s importance in host cell and microbiota crosstalk for immune cell regulation under physiologic conditions, it will be interesting to see if it also plays a similar role in IBD, gastric cancer, and other gastrointestinal diseases.

Furthermore, it will be fascinating to determine which of the mechanistic functions and regulatory pathways described above are most critical for Cdc42’s impact on gastric health and disease, as these could have profound implications for therapeutic intervention.

Check out Cytoskeleton's Cdc42 Biochem kit here, in addition to our Cdc42 learning resources here.

References

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4. Kaur, S., et al., Potential biomarkers in early detection of gastric cancer. Front Pharmacol, 2025. 16: p. 1642927.

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7. Ladinsky, M.S., et al., Endocytosis of commensal antigens by intestinal epithelial cells regulates mucosal T cell homeostasis. Science, 2019. 363(6431).

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9. Sakamori, R., et al., Cdc42 and Rab8a are critical for intestinal stem cell division, survival, and differentiation in mice. J Clin Invest, 2012. 122(3): p. 1052-65.

10. Zhang, Z., et al., CDC42 controlled apical-basal polarity regulates intestinal stem cell to transit amplifying cell fate transition via YAP-EGF-mTOR signaling. Cell Rep, 2022. 38(2): p. 110009.

11. Zhang, D., et al., Monogenic deficiency in murine intestinal Cdc42 leads to mucosal inflammation that induces crypt dysplasia. Genes Dis, 2024. 11(1): p. 413-429.

12. Cho, H.S., et al., Structure of gut microbial glycolipid modulates host inflammatory response. Cell, 2025. 188(19): p. 5295-5312 e18.

13. Li, X., et al., Role of Rho GTPases in inflammatory bowel disease. Cell Death Discov, 2023. 9(1): p. 24.

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15. Liu, L., et al., Cell division control 42 elevates during infliximab therapy, and its increment relates to treatment response in ulcerative colitis patients. J Clin Lab Anal, 2022. 36(6): p. e24477.

16. Hu, Q., et al., Paeoniflorin alleviates DSS-induced ulcerative colitis by suppressing inflammation, oxidative stress, and apoptosis via regulating serum metabolites and inhibiting CDC42/JNK signaling pathway. Int Immunopharmacol, 2024. 142(Pt A): p. 113039.

17. Stojanovic, M., et al., Hyperglycemia alters the gene and protein expression of CDC42 in small and large intestine of Sprague-Dawley rats. Mol Cell Biochem, 2026.

18. Wang, D.N., et al., Bacterial infection promotes tumorigenesis of colorectal cancer via regulating CDC42 acetylation. PLoS Pathog, 2023. 19(2): p. e1011189.

19. Liu, M., et al., miR-137 targets Cdc42 expression, induces cell cycle G1 arrest and inhibits invasion in colorectal cancer cells. Int J Cancer, 2011. 128(6): p. 1269-79.

20. Liu, M., et al., miR-185 targets RhoA and Cdc42 expression and inhibits the proliferation potential of human colorectal cells. Cancer Lett, 2011. 301(2): p. 151-60.

21. Liang, X., et al., Depletion of LINC01133 from cancer-associated fibroblasts exacerbates the progression of gastric adenocarcinoma. iScience, 2025. 28(12): p. 113886.

22. Gomez Del Pulgar, T., et al., Cdc42 is highly expressed in colorectal adenocarcinoma and downregulates ID4 through an epigenetic mechanism. Int J Oncol, 2008. 33(1): p. 185-93.

23. Al-Tassan, N.A., et al., A new GWAS and meta-analysis with 1000Genomes imputation identifies novel risk variants for colorectal cancer. Sci Rep, 2015. 5: p. 10442.

24. Fan, H., et al., Urine proteomic signatures predicting the progression from premalignancy to malignant gastric cancer. EBioMedicine, 2022. 86: p. 104340.

25. Sakamori, R., et al., CDC42 inhibition suppresses progression of incipient intestinal tumors. Cancer Res, 2014. 74(19): p. 5480-92.

26. Valdes-Mora, F., et al., Clinical relevance of the transcriptional signature regulated by CDC42 in colorectal cancer. Oncotarget, 2017. 8(16): p. 26755-26770.

27. Ma, L.L., et al., Cdc42 subcellular relocation in response to VEGF/NRP1 engagement is associated with the poor prognosis of colorectal cancer. Cell Death Dis, 2020. 11(3): p. 171.

28. Du, D.S., et al., Effects of CDC42 on the proliferation and invasion of gastric cancer cells. Mol Med Rep, 2016. 13(1): p. 550-4.

29. Wang, Q., et al., MICAL2 contributes to gastric cancer cell migration via Cdc42-dependent activation of E-cadherin/beta-catenin signaling pathway. Cell Commun Signal, 2022. 20(1): p. 136.