Chong Zhao

Targeting ferroptosis has emerged as a promising anti-cancer strategy. A Food and Drug Administration (FDA)-approved drug, sulfasalazine (SAS), also a ferroptosis inducer, is being explored as a potential treatment drug for cancer. However, long-term high-dose SAS treatment may induce several adverse effects in the liver. Our current study found that ursolic acid (UA), derived from traditional medicinal plants, fruits, and vegetables, enhanced the anti-tumor effects of low-dose SAS both in vitro (SMMC-7721 liver cells) and in vivo (a mouse tumor xenograft model). Treatment with a combination of UA and SAS reduced the glutathione (GSH), glutathione peroxidase 4 (GPX4), and promoted a substantial accumulation of lipid reactive oxygen species (ROS), leading to oxidative stress and ferroptosis. Mechanistically, the UA/SAS treatment significantly reduced the system xc− activity and cystine uptake, attributed to the AMPK activation-induced formation of the SLC7A11-BECN1 complex. Moreover, the induction of NCOA4-mediated ferritinophagy also played a role in this process. Besides, UA sensitized hepatoma cells to erastin as well, another SLC7A11-targeting ferroptosis inducer, implying a potential use of UA as a SLC7A11-targeting enhancer to combat hepatocellular carcinoma (HCC).

Metabolic dysfunction-associated steatohepatitis (MASH), an advanced manifestation of metabolic dysfunction-associated steatotic liver disease (MASLD), affects approximately 30% of adults worldwide. Fatty acids, as important nutrients, are absorbed and utilized in a complex mixture daily. Medium-chain fatty acids are recommended for patients with lipid metabolism disorders due to their favorable metabolic properties and linoleic acid (LA-l, an essential fatty acid) is commonly consumed, but their combined effects in MASH remain unclear. Therefore, in this study, we employed multi-level models and lipidomics to investigate the combined effects of lauric acid (LA-m) and LA-l under normal and MASH conditions. The results revealed that co-intake of LA-m and LA-l exacerbated hepatotoxicity specifically in MASH, but not in healthy conditions, indicating metabolic status may determine susceptibility. Mechanistically, this combination increased membrane sphingolipid accumulation under the MASH diet, inducing endoplasmic reticulum stress, and ultimately triggering hepatotoxicity. Moreover, the combination increased ACSL4 expression to generate AA/AdA-PE, suggesting that LA-m may make hepatocytes more sensitive to ferroptosis by promoting the esterification of LA-l. Collectively, these findings provide caution in the concomitant use of LA-m and LA-l in MASH patients.

Background: Cuproptosis is a form of copper-dependent non-apoptotic cell death. Cancer cells that prefer to use aerobic glycolysis for energy generation are commonly insensitive to cuproptosis, which hinders its application for cancer treatment. Epigallocatechin gallate (EGCG) possesses diverse pharmacological activities. However, the association between EGCG and cuproptosis has not been studied. Methods: The cell viability, proliferation, and cuproptosis-related protein levels were detected to investigate whether EGCG enhances the sensitivity of HCC cells to cuproptosis. The intracellular copper level, related copper metabolism proteins, and gene expression were detected to explore the mechanisms. In addition, a nude mouse xenograft model was established to determine the effects of EGCG on cuproptosis in tumor tissues. Results: The combination of EGCG and copper ionophores significantly enhanced the mortality of HCC cells and heightened the sensitivity of HCC cells to cuproptosis. There was a notable reduction in the expression of copper export protein copper-transporting P-type ATPase (ATP7B). EGCG effectively suppressed metal regulatory transcription factor (MTF1) expression and subsequently hindered the transcriptional regulation of ATP7B. EGCG also facilitated the intratumoral accumulation of copper and augmented susceptibility to cuproptosis in vivo. Conclusions: EGCG can increase the sensitivity of hepatocellular carcinoma cells to cuproptosis by promoting intracellular copper accumulation through the MTF1/ATP7B axis.

Background: Inducing ferroptosis in cancer cells is a promising therapeutic strategy. It has been shown that certain types of fatty acids can induce ferroptosis in multiple types of cancer cells. Methods: Here, we employed crystal violet staining and CCK8 to assess cell viability, a Liperfluo probe and commercial kit to measure lipid peroxides, and western blotting and RNA interference to detect protein levels. Results: This study demonstrates for the first time that the medium-chain fatty acids lauric acid (LA-m), octanoic acid (OA-m), and decanoic acid (DA-m) selectively sensitize various cancer cell types to ferroptosis induced by either RSL3, a well-known inducer of ferroptosis, or linoleic acid (LA-l), a ω-6 polyunsaturated fatty acid (PUFA). Mechanistically, the ferroptosis-sensitizing effect of medium-chain fatty acids is associated with their ability to upregulate cluster of differentiation 36 (CD36) and acyl-CoA synthetase long-chain family member 4 (ACSL4) expression. Conclusions: These findings suggest that medium-chain fatty acids could be developed as novel ferroptosis sensitizers to enhance ferroptosis-based cancer therapy.

Acute kidney injury (AKI) is a common clinical problem with high morbidity and mortality. The discovery of ferroptosis has provided novel insights into the mechanisms underlying AKI and paves the way for developing ferroptosis-based approaches to treat AKI. Glycyrol (GC) is a representative coumarin compound isolated from licorice that demonstrates various pharmacological activities. However, its potential for a protective effect against kidney injury remains unknown. We hypothesized that GC might be able to protect against AKI via suppression of ferroptosis. This hypothesis was tested in a cell-culture model of RSL3-induced nephrocyte ferroptosis and a mouse model of folic acid-induced AKI. The results showed that GC exerted a significant protective effect against nephrocyte ferroptosis in vitro and was effective against folic acid-induced AKI in vivo, where it was mechanistically associated with suppressing HO-1-mediated heme degradation. Collectively, the findings of the present study support the hypothesis that GC holds considerable potential to be developed as a novel agent for treating ferroptosis-related AKI.

Contamination by toxic substances is a major global food safety issue, which poses a serious threat to human health. Mycotoxins are major class of food contaminants, mainly including aflatoxins (AFs), zearalenone (ZON), deoxynivalenol (DON), ochratoxin A (OTA), fumonisins (FBs) and patulin (PAT). Ferroptosis is a newly identified iron-dependent form of programmed or regulated cell death, which has been found to be involved in diverse pathological conditions. Recently, a growing body of evidence has shown that ferroptosis is implicated in the toxicities induced by certain types of food-borne mycotoxins, which provides novel mechanistic insights into mycotoxin-induced toxicities and paves the way for developing ferroptosis-based strategy to combat against toxicities of mycotoxins. In this review article, we summarize the key findings on the involvement of ferroptosis in mycotoxin-induced toxicities and propose issues that need to be addressed in future studies for better utilization of ferroptosis-based approach to manage the toxic effects of mycotoxin contamination.