An oncogenic JMJD6-DGAT1 axis tunes the epigenetic regulation of lipid droplet formation in clear cell renal cell carcinoma

Nanointegrative In Situ Reprogramming of Tumor-Intrinsic Lipid Droplet Biogenesis for Low-Dose Radiation-Activated Ferroptosis Immunotherapy

“…Lipid droplets are highly dynamic organelles that play crucial roles in cellular adaptation to various nutrient or oxidative stresses . Interestingly, increasing evidence demonstrates that lipid droplets are key mediators of tumor resistance to chemotherapy and radiotherapy, substantiating the potential utility of lipid droplet metabolism as a promising target for abolishing the intrinsic treatment resistance of tumor cells. ,, Increasing evidence demonstrates that lipid droplets are key mediators of tumor resistance to chemotherapy and radiotherapy. − Indeed, there are reports that radiotherapy can induce the hyperactivation of HIF-1α in tumors through oxygen depletion and thus promote FABP3 and FABP7 expression to enhance LD biogenesis as a pro-survival mechanism in the context of IR-induced cellular stress. ,, To investigate if the nanoassembly-mediated siHIF-1α delivery to tumor cells could inhibit post-IR lipid droplet biogenesis, first we monitored the alterations in the expression levels of key markers in the HIF-1α-FABP3/7 signaling axis via WB assay (Figures I and S6A–C). Notably, the siHIF-1α-free IR group induced a significant upregulation of HIF-1α and activated the downstream FABP3/7 signal axis, which was attributed to the oxygen consumption during the generation of IR-induced ROS in tumor cells.…”

“…Nevertheless, clinical observations have revealed that LDR-evoked systemic tumor rejection is still rare due to insufficient radiation dose accumulation in tumor tissues and tumor-intrinsic radioresistant mechanisms, highlighting the necessity to develop treatment strategies that could sensitize tumor cells to LDR-mediated antitumorigenic effects. ,− Particularly, the hypoxic TME could activate the HIF-1α signaling axis in tumor cells to induce the upregulation of expression of fatty acid transporters FABP3 and FABP7, which would further promote fatty acid uptake and lipid storage to enhance tumor-intrinsic lipid droplet biogenesis. − From a biochemical perspective, lipid droplets are lipid-storage organelles capable of interacting with membrane-enclosed organelles for enabling efficient and bidirectional lipid transfer, thus maintaining phospholipid homeostasis of these organelles to prevent lipotoxicity during various stress events. − Furthermore, recent studies have revealed that lipid droplets are master regulators of tumor cell sensitivity to ferroptosis, ,,− a nonapoptotic form of regulated cell death characterized by the excessive accumulation of lethal lipid peroxides. − Specifically, lipid droplets could modulate the ferroptotic response of tumor cells through scavenging oxidation susceptible polyunsaturated fatty acids (PUFAs). ,, Considering the universal presence of PUFA-containing phospholipids as vital structural components in various lipid membrane structures such as cytoplasmic membrane and mitochondria, it is postulated that depleting lipid droplets in tumor cells could not only promote the ferroptosis-associated peroxidation of membrane lipids in the context of IR-upregulated ROS stress to amplify the treatment-induced direct cytotoxicity but also impair the membrane integrity to facilitate the subsequent release of tumor-derived immunogenic materials including TAAs and damage-associated molecular patterns (DAMPs) and activate the antitumorigenic immune reactions. Therefore, we hypothesize that the strategic combination of tumor targeted inhibition of lipid droplet biogenesis and LDR could synergize IR-induced direct tumor cell damage and an immunostimulatory effect to enable robust and systemic tumor regression.…”

Metabolomics Reveals Gut Microbiota Contribute to PPARα Deficiency-Induced Alcoholic Liver Injury

“…In addition, Dgat1 could promote lipid droplet accumulation, while the inhibition of Dgat1 could decrease the formation of lipid droplets in vitro. 48 Treated with ACC inhibitors and co-treated with Dgat2 inhibitor could improve non-alcoholic fatty liver disease by decreasing serum triglycerides. 49 In this study, we found that 4-HPA could decrease the level of TG and MDA in the liver and the level of ALT in the plasma on ALD by regulating inflammation and lipid metabolism.…”

The lipid droplet in cancer: From being a tumor‐supporting hallmark to clinical therapy

“…Abnormal lipid accumulation, including high levels of lipid synthesis and LD accumulation, causes various human diseases, 40 especially cancer 24 . The de novo synthesis of FAs exhibits a high incidence rate in invasive cancer 41 ; moreover, lipid uptake increases to compensate for the lack of endogenous lipid production 42 . Early studies have indicated that tumor cells tend to be accompanied by an increasing number of LDs in the hypoxic and acidic tumor environment 25 .…”