Moxibustion regulates KDM4D expression and modulates lipid metabolism to inhibit tumor proliferation in CAC mice.

Background: Lysine demethylase 4D (KDM4D) and aberrant lipid metabolism are implicated in the development and progression of colitis-associated cancer (CAC). Moxibustion, a therapeutic approach in traditional Chinese medicine, can inhibit intestinal inflammation and improve the intestinal mucosa.

Methods: Mice were intraperitoneally injected with AOM, and three cycles of 3-2-2% DSS-free drinking water were administered to establish a CAC mouse model. Moxibustion and KDM4D inhibitor 5-c-8HQ intervention were performed for 30 days after modeling was completed. IHC staining was used to observe the expression of the nuclear-associated antigen Ki67 (Ki67), proliferating cell nuclear antigen (PCNA), and IL-33 in the colon. The expression of colon KDM4D and β-Catenin was observed by immunofluorescence staining and RT‒qPCR. LC‒MS pseudotargeted metabolomic sequencing was used to semiquantitatively detect the expression levels of lipids.

Results: Moxibustion inhibited the proliferation of colon tumors in CAC mice, improved histopathology, and reduced the expression of PCNA and Ki67 in the colon. Using kdm4d knockout technology, it was initially confirmed that kdm4d is a key gene affecting CAC tumor proliferation. The inhibition of colon tumor proliferation in CAC mice by moxibustion is associated with the suppression of abnormal activation of the colon KDM4D/β-Catenin signaling pathway. LC-MS-targeted metabolomics revealed abnormal lipid metabolism in the colons of CAC mice. Moxibustion may affect the cholinergic metabolism pathway in the colon of CAC mice and regulate lipids such as sphingomyelin SM (d18:1/26:0) and triacylglycerol TAG58:7 (18:0). After kdm4d knockout, lipid disorders in the colons of CAC mice were partially restored. The kdm4d gene may be involved in the mechanism underlying the effect of moxibustion on lipid metabolism in the CAC colon.

Conclusions: Moxibustion inhibited the proliferation of colon tumors in CAC mice, inhibited the activation of the tumor-promoting signaling pathway KDM4D/β-Catenin, and improved lipid metabolism disorders in the colon, thus providing a promising strategy for the clinical adjuvant treatment of colorectal cancer.