Page 171 - EJMO-9-2

Eurasian Journal of
Medicine and Oncology Genetic insights into CAD drug targets

unwinds G-quadruplex (G4) structures, contributing to the LPL is a key enzyme in lipid metabolism. It hydrolyzes
regulation of G4. Studies using xenograft tumor models triglycerides in chylomicrons and very low-density
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in mice have demonstrated that lentiviral knockdown of lipoproteins, providing free fatty acids for oxidation and
DHX36 leads to increased tumor growth and cancer cell utilization in the heart and other tissues, as well as storage
invasion while reducing apoptosis. Moreover, DHX36 in adipose tissue. A meta-analysis on LPL polymorphism
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knockout is lethal to embryos, which exhibit signs of cellular and CAD risk confirmed that the LPL polymorphism
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degeneration during early embryonic development (E7.5). HindIII HH genotype and H allele genotype are significantly
A study aimed at identifying coronary artery disease (CAD) associated with CAD risk, and the Ser447XXX genotype
biomarkers found that several loci, including DHX36, are is also significantly associated with CAD risk. This is
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causally associated with CAD, and the proteins encoded consistent with our findings, which support targeting LPL
by these genes are related to specific biological functions for the treatment of CA.
such as blood coagulation and lipid metabolism. 29,30 Our For the predicted drugs, we further analyzed their
PheWAS analysis found that DHX36 was not significantly
associated with other phenotypes at the gene level. potential side effects and the possibility of repurposing
Although the PheWAS analysis did not reveal a significant potential to enhance clinical relevance. Lovastatin is a
association between DHX36 and other phenotypes, it is cholesterol-lowering drug with common side effects,
important to consider the potential side effects related to including muscle pain, liver enzyme abnormalities, and
these phenotypes that may arise when targeting DHX36 gastrointestinal issues. Emerging studies suggest that it
for treatment. Furthermore, mediation analysis through may possess anti-inflammatory properties and help reduce
metabolites indicated that imidazole lactate levels can cardiovascular events, particularly in the context of CA,
partially offset the direct positive effect of DHX36 on CA. though further investigation is warranted. Alendronate is
Therefore, drug development targeting DHX36 appears used for osteoporosis treatment, with common side effects,
promising, and further studies are required to elucidate the such as gastrointestinal irritation and musculoskeletal
mechanisms by which DHX36 influences CA risk. pain. Studies indicate that it may provide cardiovascular
protection by reducing vascular calcification, though
TNF is a cachectin primarily produced by activated its potential role in CAD requires further exploration.
monocytes and macrophages, with endothelial cells, Stearic acid, a saturated fatty acid, may increase the risk
adipocytes, mast cells, T lymphocytes, and smooth muscle of cardiovascular disease when consumed in excess. While
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cells also producing small amounts of TNF. In a study there is limited evidence supporting its direct therapeutic
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by Andersson et al., increased plasma TNF levels were effect in CA, its involvement in fatty acid metabolism
associated with the size of atherosclerotic plaques in warrants further investigation. IBMX is used to enhance
70-year-old subjects. Among elderly patients, statin therapy the effects of certain therapies and may improve endothelial
was found to reduce the length, thickness, and number of function, which could benefit CA. However, additional
carotid atherosclerotic plaques, which coincided with a research is necessary to explore its repurposing potential
decrease in plasma TNF levels. It is widely recognized for cardiovascular disease treatment. Artemisinin,
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that pathophysiologically, different categories of cytokines primarily used for malaria treatment, has a good safety
contribute to the instability of atherosclerotic plaques, profile for short-term use but may cause liver toxicity with
thereby triggering myocardial infarction. Specifically, the prolonged use. It has potential cardiovascular benefits,
TNF and interleukin (IL1) families are involved in the particularly through anti-inflammatory mechanisms, but
accumulation of inflammatory cells, platelet aggregation, further research is warranted to validate its role in CA.
formation of vulnerable plaques, apoptosis of myocardial
cells, and adverse remodeling following myocardial Despite the significant clinical potential of these drug
infarction. At present, various inhibitors targeting the targets, integrating them into clinical practice remains
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TNF family (such as adalimumab and infliximab) are challenging. Translating these findings into treatment
used to treat multiple inflammatory and autoimmune strategies requires targeted clinical trials, where patient
diseases by blocking TNF activity. 35-37 Our study found stratification based on genetic risk, inflammatory markers
that artemisinin exhibited good binding affinity with (e.g., TNF-α levels), and lipid profiles could help identify
TNF. In recent years, the anti-inflammatory potential of those most likely to benefit. For instance, TNF-targeting
artemisinin and its derivatives has gained considerable drugs (e.g., artemisinin) could be prioritized for patients
attention, as artemisinin can inhibit the expression of with elevated inflammatory markers, particularly those
various pro-inflammatory cytokines, such as TNF-α and with persistent cardiovascular risk despite statin therapy.
IL-1β. 38,39 Based on our findings, applying artemisinin in Similarly, LPL-targeting therapies could be incorporated
the treatment of CA warrants further exploration. into lipid management plans, particularly for individuals

Volume 9 Issue 2 (2025) 163 doi: 10.36922/ejmo.7387