Page 28 - ARNM-3-2

Advances in Radiotherapy
& Nuclear Medicine Lipid-radiotherapy crosstalk in cancer

rate from cardiovascular diseases, while HDL cholesterol regulatory element-binding protein 1 (SREBP1) serves
levels are negatively correlated with cardiovascular disease as a master regulator, critically governing cholesterol
mortality. However, limited studies investigate whether synthesis, fatty acid metabolism, and the delicate balance
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lipid abnormalities affect cardiovascular diseases following of lipid homeostasis. The phosphatidylinositol 3-kinase
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radiotherapy. (PI3K)/protein kinase B (AKT)/mammalian target of
rapamycin (mTOR) signaling pathway is critical in
A cohort study by Goldberg et al. assessed lipid levels
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in 4,115 pediatric cancer survivors who had survived at promoting the expression and activity of SREBP1 and
fatty acid synthase (FASN), fostering heightened lipid
least 5-year post-treatment to evaluate the prevalence of synthesis that drives tumor cell resistance to radiotherapy.
specific lipid abnormalities and related cardiovascular risks. 31
The results indicated that abnormal non-HDL cholesterol A comprehensive review by Mousavikia et al., analyzing
levels increased the risk of stroke and peripheral vascular 27 preclinical studies and five clinical trials on colorectal
disease in patients who received radiotherapy (p=0.02). cancer, underscored the potential of PI3K/AKT/mTOR
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A retrospective study by Cheng et al. included 694 head- pathway inhibition to significantly amplify radiotherapy
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and-neck cancer patients and analyzed the incidence of efficacy through mechanistic interference with lipid
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carotid artery stenosis after radiotherapy, with a follow-up metabolism pathways. In a groundbreaking study, Li
et al. performed comprehensive western blot analyses on
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period of 1 – 3 years. Multivariate analysis showed that prostate cancer cells subjected to radiotherapy, quantifying
hypercholesterolemia (odds ratio: 1.82, 95% confidence the protein expression levels of PI3K, phosphorylated PI3K,
interval, 0.97 – 3.41, p=0.06) was associated with carotid AKT, phosphorylated AKT, mTOR, and phosphorylated
artery stenosis after radiotherapy. 28
mTOR – key signaling molecules in oncogenic pathways.
A cohort study by Wang et al. analyzed 355 esophageal Their findings revealed that targeted inhibition of the PI3K/
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squamous cell carcinoma patients who received AKT/mTOR cascade significantly suppressed prostate
radiotherapy, selecting them from clinical databases. The cancer cell proliferation, triggered apoptosis, and markedly
results showed that the probability of major coronary enhanced radiosensitivity. In a pivotal discovery, Jin et al.
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events in patients without a history of hyperlipidemia demonstrated through colorectal cancer cell experiments that
was 7.1%. In contrast, in patients with a history of exogenous cholesterol-induced pronounced radioresistance
hyperlipidemia, the likelihood of major coronary events in malignant cells, underscoring the critical need for
was 92.9% (p=0.005). This suggests that hyperlipidemia, minimizing dietary cholesterol intake in patients undergoing
as a known risk factor for atherosclerosis, increases the radiotherapy. Their groundbreaking research further
incidence of major coronary events after radiotherapy. 29 unveiled that silencing the SREBP1/FASN signaling pathway
significantly inhibited colorectal cancer cell proliferation
4. Mechanisms of lipid metabolism and triggered accelerated apoptosis following radiation
disorders on the effects of radiotherapy exposure. 33

In the preceding sections, we have synthesized evidence 4.2. Ferroptosis and lipid oxidation
demonstrating radiotherapy-induced alterations in blood
lipid profiles among cancer patients and the consequential Ferroptosis, a distinct form of regulated cell death, orchestrates
effects of dyslipidemia on therapeutic outcomes. However, its lethal cascade through iron-driven lipid peroxidation.
mechanistic insights into lipid-mediated modulation of When iron overload converges with rampant reactive oxygen
radiotherapy efficacy remain conspicuously absent. We posit species, polyunsaturated fatty acid-containing phospholipids
that blood lipid homeostasis exerts a regulatory influence on in cellular membranes become vulnerable to relentless
radiotherapeutic responses through tumor microenvironment peroxidation. This insidious accumulation of lipid peroxides
remodeling. Emerging evidence corroborates tripartite breaches membrane structural integrity, culminating in the
interactions between tumor microenvironment dynamics, catastrophic collapse characteristic of ferroptosis.
lipid metabolism dysregulation, and radiation responsiveness. Lei et al. presented compelling genetic and
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This review systematically collates contemporary discoveries biochemical evidence to establish a definitive link between
across these interconnected domains, aiming to illuminate radiotherapy and ferroptosis. Their findings revealed that
strategic pathways for investigating lipid-driven mechanisms radiotherapy stimulates lipid peroxidation and upregulates
in radiotherapy optimization. PTGS2 expression, a pivotal biomarker of ferroptosis.
Tumor cells exposed to radiotherapy displayed hallmark
4.1. Abnormal lipid synthesis ferroptotic morphological features, including mitochondrial
Abnormal lipid synthesis encompasses excessive fatty acid condensation and heightened membrane density. Crucially,
production and disrupted cholesterol synthesis. Sterol the administration of ferroptosis inhibitors significantly

Volume 3 Issue 2 (2025) 20 doi: 10.36922/ARNM025070006