Ferroptosis is an atypical form of regulated cell death, which is different from apoptosis, necrosis, pyroptosis, and autophagy. Ferroptosis is characterized by iron-dependent oxidative destruction of cellular membranes following the antioxidant system’s failure. The sensitivity of ferroptosis is tightly regulated by a series of biological processes, the metabolism of iron, amino acids, and polyunsaturated fatty acids, and the interaction of glutathione (GSH), NADPH, coenzyme Q10 (CoQ10), and phospholipids. Elevated oxidative stress (ROS) level is a hallmark of cancer, and ferroptosis serves as a link between nutrition metabolism and redox biology. Targeting ferroptosis may be an effective and selective way for cancer therapy. The underlying molecular mechanism of ferroptosis occurrence is still not enough. This review will briefly summarize the process of ferroptosis and introduce critical molecules in the ferroptotic cascade. Furthermore, we reviewed the occurrence and regulation of reduction-oxidation (redox) for ferroptosis in cancer metabolism. The role of the tumor suppressor and the epigenetic regulator in tumor cell ferroptosis will also be described. Finally, old drugs that can be repurposed to induce ferroptosis will be characterized, aiming for drug repurposing and novel drug combinations for cancer therapy more efficiently and economically.

No abstract

Multidimensional analyses have demonstrated the presence of a unique tumor microenvironment (TME) in liver cancer. Tumor‐associated macrophages (TAMs) are among the most abundant immune cells infiltrating the TME and are present at all stages of liver cancer progression, and targeting TAMs has become one of the most favored immunotherapy strategies. In addition, macrophages and liver cancer cells have distinct origins. At the early stage of liver cancer, macrophages can provide a niche for the maintenance of liver cancer stem cells. In contrast, cancer stem cells (CSCs) or poorly differentiated tumor cells are key factors modulating macrophage activation. In the present review, we first propose the origin connection between precursor macrophages and liver cancer cells. Macrophages undergo dynamic phenotypic transition during carcinogenesis. In this course of such transition, it is critical to determine the appropriate timing for therapy and block specific markers to suppress pro‐tumoral TAMs. The present review provides a more detailed discussion of transition trends of such surface markers than previous reviews. Complex crosstalk occurs between TAMs and liver cancer cells. TAMs play indispensable roles in tumor progression, angiogenesis, and autophagy due to their heterogeneity and robust plasticity. In addition, macrophages in the TME interact with other immune cells by directing cell‐to‐cell contact or secreting various effector molecules. Similarly, tumor cells combined with other immune cells can drive macrophage recruitment and polarization. Despite the latest achievements and the advancements in treatment strategies following TAMs studies, comprehensive discussions on the communication between macrophages and cancer cells or immune cells in liver cancer are currently lacking. In this review, we discussed the interactions between TAMs and liver cancer cells (from cell origin to maturation), the latest therapeutic strategies (including chimeric antigen receptor macrophages), and critical clinical trials for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) to provide a rationale for further clinical investigation of TAMs as a potential target for treating patients with liver cancer.

Zinc finger proteins are transcription factors with the finger domain, which plays a significant role in gene regulation. As the largest family of transcription factors in the human genome, zinc finger (ZNF) proteins are characterized by their different DNA binding motifs, such as C2H2 and Gag knuckle. Different kinds of zinc finger motifs exhibit a wide variety of biological functions. Zinc finger proteins have been reported in various diseases, especially in several cancers. Hepatocellular carcinoma (HCC) is the third leading cause of cancer-associated death worldwide, especially in China. Most of HCC patients have suffered from hepatitis B virus (HBV) and hepatitis C virus (HCV) injection for a long time. Although the surgical operation of HCC has been extremely developed, the prognosis of HCC is still very poor, and the underlying mechanisms in HCC tumorigenesis are still not completely understood. Here, we summarize multiple functions and recent research of zinc finger proteins in HCC tumorigenesis and progression. We also discuss the significance of zinc finger proteins in HCC diagnosis and prognostic evaluation.

3,4-Dihydroxybutyric acid (3,4-DHBA) is an important platform chemical with versatile applications. Traditional chemical approaches for 3,4-DHBA production involving hazardous materials and harsh reaction conditions are environmentally unfriendly. The reported biotechnological routes for 3,4-DHBA production rely on microbial monocultures with low productivity and yield. In this study, a coculture system to synthesize 3,4-DHBA from xylose was established using Gluconobacter oxydans and Escherichia coli. First, it was confirmed that G. oxydans 621H can oxidize xylose and 3,4-dihydroxybutanal (3,4-DHB) into xylonate and 3,4-DHBA, respectively. Second, xylonate dehydratase and α-ketoisovalerate decarboxylase were overexpressed and the competing pathways in the host strain were knocked out for 3,4-DHB biosynthesis from xylonate in E. coli. Third, the conditions for the coculture of G. oxydans 621H and engineered E. coli were optimized to enhance 3,4-DHBA biosynthesis from xylose. Finally, the coculture system produced 3.26 g/L 3,4-DHBA from 7.0 g/L xylose with a high yield of 0.47 g/g, achieving the highest titer and yield of 3,4-DHBA reported so far. Besides the biotechnological production of 3,4-DHBA, the coculture of G. oxydans 621H with engineered E. coli would be a useful engineering strategy in the production of other important biochemicals.

No abstract

Emerging evidence suggests that ferroptosis is involved in the pathogenesis of ulcerative colitis (UC).However, the key regulator of this process remains uncertain. In this study, we aimed to explore the roles of solute carrier (SLC) family 6 member 14 (SLC6A14) in regulating ferroptosis in UC. The expression of SLC6A14 was signi cantly increased and positively associated with that of prostaglandin-endoperoxide synthase 2 (PTGS2) in tissue samples from patients with UC. Moreover, a series of in vitro and in vivo experiments showed that SLC6A14 knockdown markedly suppressed ferroptosis. RNA sequencing revealed that SLC6A14 inhibited the expression of P21 (RAC1) activated kinase 6 (PAK6) and that PAK6 knockdown abolished the effects of SLC6A14 on RAS-selective lethal 3 (RSL3) -induced ferroptosis in Caco-2 cells. Furthermore, chromatin immunoprecipitation (ChIP) and Western blot analysis demonstrated that SLC6A14 negatively regulated PAK6 expression in a CCAAT enhancer binding protein beta (C/EBPβ)-dependent manner. Collectively, these ndings indicate that SLC6A14 facilitates ferroptosis in UC by promoting C/EBPβ expression and binding activity to inhibit PAK6 expression, suggesting that targeting SLC6A14-C/EBPβ-PAK6 axis-mediated ferroptosis may be a promising therapeutic alternative for UC.

Background Genetic background plays an important role in the occurrence and development of gastric cancer (GC). With the application of genome-wide association study (GWAS), an increasing number of tumor susceptibility genes in gastric cancer have been discovered. While little of them can be further applicated in clinical diagnosis and treatment due to the lack of in-depth analysis. Methods A GWAS of peripheral blood leukocytes from GC patients was performed to identify and obtain genetic background data. In combination with a clinical investigation, key SNP mutations and mutated genes were screened. Via in vitro and in vivo experiments, the function of the mutated gene was verified in GC. Via a combination of molecular function studies and amino acid network analysis, co-mutations were discovered and further identified as potential therapeutic targets. Results At the genetic level, the G allele of rs104886038 in DHCR7 was a protective factor identified by the GWAS. Clinical investigation showed that patients with the rs104886038 A/G genotype, age ≥ 60, smoking ≥ 10 cigarettes/day, heavy drinking and H. pylori infection were independent risk factors for GC, with odds ratios of 12.33 (95% CI, 2.10 ~ 72.54), 20.42 (95% CI, 2.46 ~ 169.83), and 11.39 (95% CI, 1.82 ~ 71.21), respectively. Then molecular function studies indicated that DHCR7 regulated cell proliferation, migration, and invasion as well as apoptosis resistance via cellular cholesterol biosynthesis pathway. Further amino acid network analysis based on the predicted structure of DHCR7 and experimental verification indicated that rs104886035 and rs104886038 co-mutation reduced the stability of DHCR7 and induced its degradation. DHCR7 mutation suppressed the malignant behaviour of GC cells and induced apoptosis via inhibition on cell cholesterol biosynthesis. Conclusion In this work, we provided a comprehensive multi-dimensional analysis strategy which can be applied to in-depth exploration of GWAS data. DHCR7 and its mutation sites identified by this strategy are potential theratic targets of GC via inhibition of cholesterol biosynthesis.