Hypoxia-Driven Mitochondrial Enzyme Helps Pancreatic Cancer Evade Ferroptosis and Resist Gemcitabine

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal human malignancies, with a five-year relative survival rate of approximately 13 percent. Despite decades of therapeutic development, gemcitabine-based chemotherapy continues to face profound intrinsic and acquired resistance, constraining durable disease control across all stages of the disease. Now, a new translational study published in Frontiers in Cell and Developmental Biology has identified a hypoxia-responsive mitochondrial enzyme as a key molecular bridge between the oxygen-starved tumor microenvironment and the evasion of ferroptosis, an iron-dependent form of regulated cell death driven by phospholipid peroxidation.

The research team, led by investigators at Sichuan Provincial People’s Hospital in Chengdu, China, focused on sulfide:quinone oxidoreductase (SQOR), a flavoprotein embedded in the inner mitochondrial membrane. SQOR catalyzes the first committed step of hydrogen sulfide (H₂S) oxidation and transfers the resulting electrons to coenzyme Q (CoQ), generating the reduced antioxidant form CoQH₂. This biochemical position makes SQOR a plausible link between hypoxic metabolic adaptation, CoQH₂ availability, and suppression of lipid peroxidation, yet its role in pancreatic cancer had remained undefined.

Using a tissue microarray from 102 patients with PDAC, the researchers found that SQOR protein abundance showed moderate positive associations with the hypoxia markers carbonic anhydrase IX (CAIX) and hypoxia-inducible factor 1α (HIF-1α), with Spearman correlation coefficients of 0.473 and 0.438 respectively. Conversely, SQOR levels were inversely associated with 4-hydroxynonenal (4-HNE), a marker of lipid peroxidation, with a correlation coefficient of −0.465. Higher SQOR abundance was also associated with shorter overall survival after multivariable adjustment for GPX4 and FSP1, yielding an adjusted hazard ratio of 1.87.

Mechanistic experiments in PANC-1 and MIA PaCa-2 cells revealed that hypoxia increased SQOR expression and shifted the CoQH₂/total CoQ ratio upward by approximately 1.6-fold at 24 hours, while suppressing lipid peroxidation. These effects required SQOR catalytic activity rather than protein abundance alone, as a catalytically inactive mutant phenocopied SQOR knockdown. Electron-donor testing implicated hydrogen sulfide more strongly than selenium metabolism under the tested conditions, with H₂S donors increasing the reduced CoQ fraction in a dose-dependent manner and inhibition of the H₂S-producing enzymes CBS and CSE blunting the hypoxia-associated CoQ shift.

Lipidomic profiling showed that SQOR loss increased relative signals annotated as oxidized arachidonoyl- and adrenoyl-phosphatidylethanolamines, lipid species directly implicated as proximal ferroptotic death signals. Pathway-epistasis experiments demonstrated that SQOR loss synergized with inhibition of GPX4, FSP1, and DHODH, supporting a nonredundant contribution to ferroptosis control. Death-mode rescue assays showed that ferroptosis-directed agents provided substantially greater protection than a caspase inhibitor, consistent with a substantial ferroptotic contribution to the observed viability loss.

Therapeutic relevance was evaluated in gemcitabine-resistant cell lines, eight patient-derived organoid lines, and xenograft models. Gemcitabine-resistant cells showed approximately 2.8-fold higher SQOR protein, a rise in the CoQH₂/total CoQ ratio from about 27 percent to 49 percent, and baseline lipid ROS at roughly half the parental level. Combining a putative SQOR inhibitor with ferroptosis induction lowered gemcitabine IC₅₀ values in resistant models by six- to sevenfold relative to untreated resistant cells, though residual resistance remained 1.9- to 2.0-fold above parental sensitivity. In patient-derived organoids, the four SQOR-high lines showed paired viability reductions of approximately 46 to 52 percentage points when the SQOR inhibitor was added to gemcitabine, whereas the SQOR-low lines showed smaller, heterogeneous changes.

In xenograft models, the combination treatment reduced day-28 tumor volume and terminal tumor weight relative to gemcitabine alone, and prolonged survival in an independent cohort, with median survival extending from 35 days with gemcitabine to 49 days with the combination. However, tumor regression was not observed, and these efficacy endpoints alone do not establish SQOR target engagement or ferroptotic tumor-cell death in vivo.

The authors emphasize that the tissue correlations are associative and do not establish that hypoxia suppresses lipid peroxidation through SQOR in patients. The retrospective single-center cohort, the use of CAIX and HIF-1α staining rather than direct oxygen measurements, and the cross-sectional nature of the H-scores limit claims about temporal ordering and causal mediation. The exploratory mixed response endpoint, which combines radiological and biochemical criteria, is treated as hypothesis-generating rather than a validated clinical measure.

These findings support further preclinical evaluation of SQOR-directed strategies to improve gemcitabine sensitivity in PDAC. The SQOR–CoQ axis adds a mitochondrial sulfur-oxidation component to the layered ferroptosis-defense network, positioning it alongside established pathways involving GPX4, FSP1, and DHODH. Prospective clinical studies, broader genetic backgrounds, continuous-marker validation, and pharmacologically characterized SQOR interventions will be needed to determine whether this axis can be translated into a clinically actionable therapeutic strategy for patients with pancreatic cancer.

The connection between hydrogen sulfide metabolism and cancer cell survival has attracted growing attention in recent years, and the present study adds an important dimension to this emerging field. Hydrogen sulfide is often thought of as a toxic environmental gas, but it is also produced endogenously by mammalian enzymes, most notably cystathionine beta-synthase and cystathionine gamma-lyase, which operate in the transsulfuration pathway that branches off the methionine cycle. Under physiological conditions, H₂S acts as a signaling molecule involved in vascular tone, oxygen sensing, and cellular stress responses. Because mitochondria are the principal site of sulfide oxidation, the clearance of this gas is tightly coupled to the respiratory chain, and SQOR sits at the entry point of that clearance pathway. By transferring electrons from sulfide onto coenzyme Q, SQOR effectively converts a potentially damaging molecule into a source of reducing equivalents, and the new findings suggest that pancreatic cancer cells exploit this reaction to keep their mitochondrial membranes in a reduced, peroxidation-resistant state.

The coenzyme Q pool occupies a central position in this scheme because it serves multiple masters simultaneously. CoQ accepts electrons from complex I and complex II during oxidative phosphorylation, from dihydroorotate dehydrogenase during pyrimidine biosynthesis, and from sulfide oxidation through SQOR. The reduced form, CoQH₂, is itself a lipid-soluble radical-trapping antioxidant that can terminate lipid peroxidation chain reactions directly in membranes. This dual role explains why the same pool that fuels respiration can also suppress ferroptosis, and why the ferroptosis defenses mediated by FSP1 at the plasma membrane and DHODH in mitochondria both converge on CoQ reduction. The study’s epistasis experiments, showing that SQOR loss synergizes with inhibition of all three established defense systems, are consistent with this picture of partially independent but functionally overlapping layers of protection, each buffering lipid peroxides in a different cellular compartment.

The lipidomic observations deserve particular attention in this context. Phosphatidylethanolamines bearing polyunsaturated fatty acyl chains such as arachidonate are widely regarded as preferred substrates for the oxidative reactions that drive ferroptosis, and their oxidized products are among the most frequently cited death signals in the field. The finding that SQOR loss preferentially increased signals annotated as oxidized arachidonoyl- and adrenoyl-phosphatidylethanolamines therefore links the mitochondrial redox state to the specific molecular species most closely associated with ferroptotic execution. It is worth noting, as the authors do, that these are relative signals from untargeted lipidomics, and targeted validation of the individual oxidized species would strengthen the mechanistic chain from enzyme activity to membrane chemistry.

The hypoxic biology of pancreatic tumors provides a plausible rationale for why this pathway might be selected for during tumor evolution. Direct oxygen electrode measurements in human pancreatic cancers have documented some of the lowest tumor oxygen tensions recorded among solid malignancies, and the dense desmoplastic stroma further limits perfusion and drug penetration. Under such conditions, conventional mitochondrial respiration is constrained, and cancer cells must rewire their redox metabolism to survive. Inducing a sulfide-dependent route of CoQ reduction would allow cells to maintain antioxidant capacity even when electron flow through the canonical respiratory chain is limited by oxygen availability. The observed correlation between SQOR and HIF-1α, the master transcriptional regulator of the hypoxic response, fits this adaptive logic, although the study’s cross-sectional design cannot resolve whether hypoxia drives SQOR expression in patients or whether the two simply co-occur as markers of aggressive disease.

The therapeutic implications hinge on several caveats that the authors handle with appropriate care. The SQOR inhibitor used in the preclinical experiments is described as putative, meaning its selectivity, potency, and pharmacokinetic properties have not been fully characterized, and off-target effects cannot be excluded. The combination strategy lowered gemcitabine IC₅₀ values in resistant models but did not restore full parental sensitivity, indicating that SQOR-directed ferroptosis priming is a partial rather than complete reversal of the resistant phenotype. Residual resistance likely reflects the many other mechanisms by which pancreatic cancer cells evade chemotherapy, including impaired drug uptake, stromal barriers, and parallel survival pathways. The xenograft results, while encouraging, showed growth delay rather than regression, a pattern typical of cytostatic combinations in early preclinical testing.

From a broader perspective, the study contributes to a growing recognition that ferroptosis sensitivity is not governed by a single switch but by a layered network whose components can be independently tuned by metabolic context. Hypoxia, sulfur amino acid availability, selenium status, and membrane lipid composition all feed into this network, and different tumors may rely on different combinations of defenses. The demonstration that a catalytically inactive SQOR mutant phenocopied knockdown is particularly valuable, because it establishes that the relevant function is enzymatic rather than structural, which is a prerequisite for inhibitor-based therapeutic strategies. Future work will need to identify whether SQOR expression can be used as a predictive biomarker to select patients most likely to benefit from ferroptosis-inducing combinations, and whether pharmacological SQOR inhibition can be achieved safely given the enzyme’s normal role in sulfide detoxification. If those questions can be answered, the SQOR–CoQ axis may offer a way to convert one of pancreatic cancer’s most stubborn microenvironmental features, its profound hypoxia, from a shield against therapy into a therapeutic vulnerability.

Subject of Research: Hypoxia-induced sulfide:quinone oxidoreductase suppresses ferroptosis and promotes gemcitabine resistance through mitochondrial coenzyme Q reduction in pancreatic ductal adenocarcinoma

Article Title: Hypoxia-induced sulfide:quinone oxidoreductase suppresses ferroptosis and promotes gemcitabine resistance through mitochondrial coenzyme Q reduction in pancreatic ductal adenocarcinoma

Article References: Huang, G., An, X., Yuan, T., & Liao, D. (2026). Hypoxia-induced sulfide:quinone oxidoreductase suppresses ferroptosis and promotes gemcitabine resistance through mitochondrial coenzyme Q reduction in pancreatic ductal adenocarcinoma. Frontiers in Cell and Developmental Biology, 14, 1971375. https://doi.org/10.3389/fcell.2026.1971375

Image Credits: AI Generated

DOI: 10.3389/fcell.2026.1971375

Keywords: SQOR, ferroptosis, pancreatic cancer, gemcitabine resistance, hypoxia, coenzyme Q, Hypoxia-induced, sulfide, quinone, oxidoreductase, suppresses, promotes