BTB domain and CNC homology 1 (BACH1) is a transcription factor that is highly expressed in tumors including breast and lung, relative to their non-tumor tissues. BACH1 is known to regulate multiple physiological processes including heme homeostasis, oxidative stress response, senescence, cell cycle, and mitosis. In a tumor, BACH1 promotes invasion and metastasis of cancer cells, and the expression of BACH1 presents a poor outcome for cancer patients including breast and lung cancer patients. Recent studies identified novel functional roles of BACH1 in the regulation of metabolic pathways in cancer cells. BACH1 inhibits mitochondrial metabolism through transcriptional suppression of mitochondrial membrane genes. In addition, BACH1 suppresses activity of pyruvate dehydrogenase (PDH), a key enzyme that converts pyruvate to acetyl-CoA for the citric acid (TCA) cycle through transcriptional activation of pyruvate dehydrogenase kinase (PDK). Moreover, BACH1 increases glucose uptake and lactate secretion through the expression of metabolic enzymes involved such as hexokinase 2 (HK2) and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) for aerobic glycolysis. Pharmacological or genetic inhibition of BACH1 could reprogram by increasing mitochondrial metabolism, subsequently rendering metabolic vulnerability of cancer cells against mitochondrial respiratory inhibition. Furthermore, inhibition of BACH1 decreased antioxidant-induced glycolysis rates as well as reduced migration and invasion of cancer cells, suggesting BACH1 as a potentially useful cancer therapeutic target.

Alterations of metabolic pathways that sustain cancer cell survival often offer promising therapeutic avenues. Here, we show that enhanced de novo cholesterol biosynthesis is crucial for the survival of head and neck squamous cell carcinoma (HNSCC). Transcriptomic analysis of HNSCC tissues identified profound dysregulation in steroid and cholesterol metabolism compared to normal tissues. Inhibition of two key enzymes, DHCR7 and DHCR24, which mediate cholesterol biosynthesis, induced apoptosis in HNSCC cells, even when cholesterol levels were restored. Metabolomic profiling revealed the accumulation of 7-dehydrocholesterol (7-DHC) upon DHCR7 or DHCR24 inhibition, triggering endoplasmic reticulum (ER) stress and promoting further cell death. These findings suggest that HNSCC cells adapt to ER stress by modulating 7-DHC levels through enhancing DHCR7 and DHCR24 levels, highlighting a metabolic vulnerability in HNSCC and demonstrating a direct link between cholesterol metabolism and ER stress in cancer cell viability.

The oncogenic expression or mutation of tumor suppressors drives metabolic alteration, causing cancer cells to utilize diverse nutrients. Lactate is a known substrate for cancer cells, yet the regulatory mechanisms of lactate catabolism are limited. Here, we show that a heme-binding transcription factor, BACH1, negatively regulates lactate catabolic pathways in triple-negative breast cancer (TNBC) cells. BACH1 suppresses the transcriptional expression of monocarboxylate transporter 1 (MCT1) and lactate dehydrogenase B, inhibiting lactate-mediated mitochondrial metabolism. In our studies, the depletion of BACH1 either genetically or pharmacologically increased the lactate use of TNBC cells, increasing their sensitivity to MCT1 inhibition. Thus, small inhibitory molecules (SR13800 and AZD3965) blocking MCT1 better suppressed the growth of BACH1-depleted TNBC cells than did the controls. Particularly, hemin treatment degrading BACH1 proteins induced lactate catabolism in TNBC cells, generating synthetic lethality with MCT1 inhibition. Our data indicates that targeting BACH1 generates metabolic vulnerability and increases sensitivity to lactate transporter inhibition, suggesting a potential novel combination therapy for cancer patients with TNBC.

Head and neck squamous cell carcinoma (HNSCC) remains a clinically challenging malignancy with limited targeted therapy options and poor patient outcomes. Thus, identifying unique dependencies, including HNSCC-specific metabolic reprogramming, is imperative for improving treatment strategies for this disease. In this study, we show that HNSCC relies on elevated glucose transporter 1 (GLUT1)–mediated glucose uptake to support redox homeostasis and tumor growth. Analyses of GLUT1 expression data in tumors and cancer cell lines reveal significant upregulation of GLUT1 in HNSCC relative to both normal tissue and other cancer subtypes and that high GLUT1 expression correlates with poorer clinical outcomes. Using a basal epithelial layer–specific GLUT1-knockout mouse model, we demonstrate that GLUT1 ablation in HNSCC cells of origin markedly attenuates tumor initiation and progression, implicating the necessity of GLUT1 in HNSCC tumorigenesis. Building on this observation, combining pharmacologic inhibition of GLUT1 with pro-oxidants such as vitamin C and auranofin induces potent cytotoxicity in vitro and in vivo, partly by precipitating oxidative stress. We further observe that insulin signaling is required to sustain glucose uptake and redox homeostasis, as insulin receptor knockdown decreases proliferation and increases reactive oxygen species levels. Together, these results suggest that although GLUT1 overexpression is a key driver of glucose uptake, insulin signaling also contributes to the metabolic and oncogenic pathways underlying HNSCC progression. Consequently, strategies that co-target GLUT1 and insulin signaling to restrict glucose flux may synergize with pro-oxidant therapies, offering a promising therapeutic avenue for HNSCC. Significance: Enhanced GLUT1 expression and oncogenic insulin signaling drive elevated glucose uptake in HNSCC, which contribute to the maintenance of redox homeostasis and tumor growth. Disrupting both glucose uptake and redox balance may offer a promising therapeutic approach.

Prostaglandin regulation is known to play a pivotal role in tumorigenesis; however, the contributions of the prostaglandin-metabolizing enzyme 15-hydroxyprostaglandin dehydrogenase (HPGD) to cancer development remain poorly understood. In this study, we investigate the effects of HPGD on cell viability, proliferation, anchorage-independent growth, and migration in triple-negative breast cancer (TNBC), an aggressive subtype of breast cancer. Overexpression of HPGD in human TNBC cells resulted in both positive and negative regulation of cell proliferation and colony formation, with these effects occurring independent of prostaglandin E2 (PGE₂). In contrast, overexpression of the mouse homolog, Hpgd, in murine TNBC cells led to a consistent but modest reduction in cell viability and colony formation, indicating that HPGD activity varies depending on species and cell line context. Notably, TNBC cells expressing a mutant form of Hpgd (Hpgd^mut), which lacks the ability to bind PGE₂, exhibited similar functional outcomes in cell viability and colony formation as those expressing wild-type Hpgd (Hpgd^WT). These findings suggest that HPGD may exert its tumorigenic effects through non-enzymatic mechanisms, potentially by involving modulation of KRAS signaling in human TNBC cells. Our results highlight the diverse roles of HPGD in cancer biology, particularly in the context of TNBC, and point to non-enzymatic pathways as a significant aspect of its tumorigenic activity.

GLUT1 inhibition enhances cytotoxic oxidative stress in human HNSCC cell lines. A,In vitro proliferation and immunoblot analyses of shScramble (shScr) and shRNA-mediated KD of GLUT1 (shGLUT1) in HNSCC cell line FaDu (n = 4 for each group). Two-way ANOVA. ****, P < 0.0001 (left). Immunoblot validation of shRNA-mediated KD of GLUT1 in FaDu cells (right). B, Relative glucose uptake and (C) intracellular ROS measurement in shScr and shGLUT1 FaDu cells (n = 3 for each group). Two-tailed t test. ***, P < 0.001; **, P < 0.01. D,In vitro proliferation of shScr, shGLUT1, and shGLUT1 + NAC (5 mmol/L) in HNSCC cell line SCC-61 (n = 4 for each group). Two-way ANOVA. ****, P < 0.0001 (left). Immunoblot validation shRNA-mediated KD of GLUT1 in SCC-61 cells (right). E, Intracellular ROS measurement of shScr, shGLUT1, and shGLUT1 + NAC (5 mmol/L) in SCC-61 cells (n = 3 for each group). Two-tailed t test. ****, P < 0.0001; ***, P < 0.001. F and G,In vitro proliferation of FaDu cells treated with GLUT1 inhibitors, WZB117 (0–40 μmol/L) or BAY-876 (0–100 nmol/L; n = 3 for each group). H and I,In vitro proliferation of FaDu (H) or SCC-61 (I) treated with WZB117 (30 μmol/L) or BAY-876 (150 nmol/L) with or without 5 mmol/L NAC treatment (n = 6 for each group). Two-way ANOVA. ****, P < 0.0001; **, P < 0.01; *, P < 0.05 (top). Intracellular H2O2 measurement of FaDu (H) or SCC-61 (I) cells treated with WZB117 (30 μmol/L) or BAY-876 (150 nmol/L) with or without 5 mmol/L NAC treatment (n = 6 for each group). Two-tailed t test. ****, P < 0.0001; ***, P < 0.001; **, P < 0.01 (bottom). All error bars represent mean ± SEM unless otherwise noted. BAY, BAY-876; RFU, relative fluorescent unit; RLU, relative light unit; WZB, WZB117.