Wild-type and cancer-related p53 proteins are preferentially degraded by MDM2 as dimers rather than tetramers.

The p53 tumor suppressor protein is the most well studied as a regulator of transcription in the nucleus, where it exists primarily as a tetramer. However, there are other oligomeric states of p53 that are relevant to its regulation and activities. In unstressed cells, p53 is normally held in check by MDM2 that targets p53 for transcriptional repression, proteasomal degradation, and cytoplasmic localization. Here we discovered a hydrophobic region within the MDM2 N-terminal domain that binds exclusively to the dimeric form of the p53 C-terminal domain in vitro. In cell-based assays, MDM2 exhibits superior binding to, hyperdegradation of, and increased nuclear exclusion of dimeric p53 when compared with tetrameric wild-type p53. Correspondingly, impairing the hydrophobicity of the newly identified N-terminal MDM2 region leads to p53 stabilization. Interestingly, we found that dimeric mutant p53 is partially unfolded and is a target for ubiquitin-independent degradation by the 20S proteasome. Finally, forcing certain tumor-derived mutant forms of p53 into dimer configuration results in hyperdegradation of mutant p53 and inhibition of p53-mediated cancer cell migration. Gaining insight into different oligomeric forms of p53 may provide novel approaches to cancer therapy.

Embracing Robotics in Microsurgery: Robotic-Assisted Deep Inferior Epigastric Perforator (DIEP) Flap Breast Reconstruction.

The integration of robotic-assisted surgery (RAS) has transformed various surgical disciplines, including more recently plastic surgery. While RAS has gained acceptance in multiple specialties, its integration in plastic surgery has been gradual, challenging traditional open methods. Robotic-assisted deep inferior epigastric perforator (DIEP) flap breast reconstruction is a technique aimed to overcome drawbacks associated with the traditional open DIEP flap approach. These limitations include a relatively large fascial incision length, potentially increasing rates of postoperative pain, abdominal bulge, hernia rates, and core weakening. The robotic-assisted DIEP flap technique emerges as an innovative and advantageous approach in fascial-sparing abdominal based autologous breast reconstruction. While acknowledging certain challenges such as increased operative time, ongoing refinements are expected to further improve the overall surgical experience, optimize results, and solidify the role of robotics in advancing reconstructive microsurgical procedures in plastic surgery. Herein, the authors provide an overview of robotic surgery in the context of plastic surgery and its role in the DIEP flap harvest for breast reconstruction.

Granulomatosis With Polyangiitis (Wegener's Granulomatosis) Nasal Reconstruction: Improved Outcomes With No Delay.

BACKGROUND: Granulomatosis with polyangiitis (Wegener's granulomatosis) causes progressive nasal collapse, nasal obstruction, and central face deformity. It is not known whether cartilaginous nasal reconstruction should be performed immediately or delayed until after disease "burnout." OBJECTIVES: The aims of this research regarding nasal collapse due to Wegener's granulomatosis were to (1) assess the functional and aesthetic outcomes following immediate vs delayed nasal reconstruction; and (2) measure the impact of psychosocial well-being (anxiety, depression, social isolation) in immediate vs delayed nasal reconstruction. METHODS: Wegener's patients with either immediate or delayed nasal surgery (n = 61) were compared. Functional and aesthetic severity were compared with the validated Standard Cosmesis and Health Nasal Outcome Survey (SCHNOS) score (t test). In addition, Patient-Reported Outcomes Measurement Information System (PROMIS) perioperative and 1-year follow-up surveys were analyzed. RESULTS: At initial consultation, SCHNOS score severity types were similar for both groups (immediate vs delayed): mild 15% vs 15%; moderate 59% vs 60%, and severe 26% vs 25%. Over a 30 ± 4 month period, delayed surgery patients' conditions deteriorated, with a shift from mild to more severe SCHNOS scores, from 25% severe at initial consultation to 85% before surgery. PROMIS scores at presentation were high compared to the general public; by the time of delayed surgery, patients had significantly worsened: anxiety from 28 to 73; depression from 18 to 62; and social isolation from 20 to 80. Although both immediate and delayed groups improved after surgery in functional and psychosocial scores, the immediate surgery group's improvement was superior. CONCLUSIONS: Data showed superior functional and aesthetic scores and superior psychosocial indicators with immediate cartilaginous nasal reconstruction, compared with waiting until disease burnout to undergo surgery.

Ethical Issues Surrounding Facial Feminization Surgery: Five Major Considerations.

Facial feminization surgery (FFS) is a form of gender-affirming care for the transgender population that is currently a highly debated topic both inside and outside of the medical community. Currently, a paucity of information is available in plastic surgery literature on ethical issues surrounding FFS. In this paper, we discuss 5 major ethical considerations for plastic surgeons with regard to FFS: (1) how society's changing view of gender has impacted the importance of FFS; (2) whether FFS is medically necessary and should be covered by insurance; (3) to what extent resources should be invested in removing barriers to access FFS; (4) how patient selection criteria should address the irreversibility of the procedure and age of consent; and (5) how femininity and beauty standards contribute to each other and whether they can be disentangled. This paper aims to analyze the arguments made for and against each of these 5 nuanced issues and to expand these debates from the theoretical to the practical by suggesting approaches for reconciliation.

Facial Feminization Surgery: Anatomical Differences, Preoperative Planning, Techniques, and Ethical Considerations.

Facial Feminization Surgery (FFS) is a transformative surgical approach aimed at aligning the facial features of transgender women with their gender identity. Through a systematic analysis, this paper explores the clinical differences between male and female facial skeletons along with the craniofacial techniques employed in FFS for each region. The preoperative planning stage is highlighted, emphasizing the importance of virtual planning and AI morphing as valuable tools to be used to achieve surgical precision. Consideration is given to special circumstances, such as procedure sequencing for older patients and silicone removal. Clinical outcomes, through patient-reported outcome measures and AI-based gender-typing assessments, showcase the efficacy of FFS in achieving proper gender recognition and alleviating gender dysphoria. This comprehensive review not only offers valuable insights into the current state of knowledge regarding FFS but also emphasizes the potential of artificial intelligence in outcome evaluation and surgical planning to further advance patient care and satisfaction with FFS.

Heart recovery from a brain-dead donor with a history of Ravitch procedure for repair of pectus excavatum.

BACKGROUND: We describe the successful heart transplantation of a brain-dead male donor with a remote history of pectus excavatum repair. METHOD AND RESULTS: On computed tomography, the ascending aorta was in close proximity to metallic struts from the donor's sternal repair. Before harvesting the heart, visual and digital inspections revealed minimal space between the sternum and ascending aorta, complicated by severe adhesions in the lower sternum. After the pericardium was opened, the subsequent recovery of the heart was performed in a standard fashion. At one-year post-transplant, the recipient continues to have normal graft function. CONCLUSIONS: Careful evaluation, intraoperative consideration, and coordination with other transplant teams were essential in the successful recovery of the heart during a time of organ shortages.

At-Home Testing for Sexually Transmitted Infections During the COVID-19 Pandemic.

During the COVID-19 pandemic in New York City, NewYork-Presbyterian Hospital provided HIV prevention patients with gonorrhea/chlamydia testing kits at home. This report describes the program implementation to provide other sexual health clinics with a roadmap in adapting to a "new normal" in providing comprehensive sexual health care virtually to patients.

Position-Dependent Effect of Guanine Base Damage and Mutations on Telomeric G-Quadruplex and Telomerase Extension.

Telomeres are hot spots for mutagenic oxidative and methylation base damage due to their high guanine content. We used single-molecule fluorescence resonance energy transfer detection and biochemical assays to determine how different positions and types of guanine damage and mutations alter telomeric G-quadruplex structure and telomerase activity. We compared 15 modifications, including 8-oxoguanine (8oxoG), O-6-methylguanine (O6mG), and all three possible point mutations (G to A, T, and C) at the 3' three terminal guanine positions of a telomeric G-quadruplex, which is the critical access point for telomerase. We found that G-quadruplex structural instability was induced in the order C < T < A ≤ 8oxoG < O6mG, with the perturbation caused by O6mG far exceeding the perturbation caused by other base alterations. For all base modifications, the central G position was the most destabilizing among the three terminal guanines. While the structural disruption by 8oxoG and O6mG led to concomitant increases in telomerase binding and extension activity, the structural perturbation by point mutations (A, T, and C) did not, due to disrupted annealing between the telomeric overhang and the telomerase RNA template. Repositioning the same mutations away from the terminal guanines caused both G-quadruplex structural instability and elevated telomerase activity. Our findings demonstrate how a single-base modification drives structural alterations and telomere lengthening in a position-dependent manner. Furthermore, our results suggest a long-term and inheritable effect of telomeric DNA damage that can lead to telomere lengthening, which potentially contributes to oncogenesis.

In Silico Performance of a Recellularized Tissue-Engineered Transcatheter Aortic Valve.

Commercially available heart valves have many limitations, such as a lack of remodeling, risk of calcification, and thromboembolic problems. Many state-of-the-art tissue-engineered heart valves (TEHV) rely on recellularization to allow remodeling and transition to mechanical behavior of native tissues. Current in vitro testing is insufficient in characterizing a soon-to-be living valve due to this change in mechanical response; thus, it is imperative to understand the performance of an in situ valve. However, due to the complex in vivo environment, this is difficult to accomplish. Finite element (FE) analysis has become a standard tool for modeling mechanical behavior of heart valves; yet, research to date has mostly focused on commercial valves. The purpose of this study has been to evaluate the mechanical behavior of a TEHV material before and after 6 months of implantation in a rat subdermis model. This model allows the recellularization and remodeling potential of the material to be assessed via a simple and inexpensive means prior to more complex ovine orthotropic studies. Biaxial testing was utilized to evaluate the mechanical properties, and subsequently, constitutive model parameters were fit to the data to allow mechanical performance to be evaluated via FE analysis of a full cardiac cycle. Maximum principal stresses and strains from the leaflets and commissures were then analyzed. The results of this study demonstrate that the explanted tissues had reduced mechanical strength compared to the implants but were similar to the native tissues. For the FE models, this trend was continued with similar mechanical behavior in explant and native tissue groups and less compliant behavior in implant tissues. Histology demonstrated recellularization and remodeling although remodeled collagen had no clear directionality. In conclusion, we observed successful recellularization and remodeling of the tissue giving confidence to our TEHV material; however, the mechanical response indicates the additional remodeling would likely occur in the aortic/pulmonary position.

Optimized biomimetic minerals maintain activity of mRNA complexes after long term storage.

mRNA therapeutics can be readily designed, manufactured, and brought to scale, as demonstrated by widespread global vaccination against COVID-19. However, mRNA therapies require cold chain shipment and storage from manufacturing to administration, which may limit them to affluent communities. This problem could be addressed by mimicking the known ability of mineralized fossils to durably stabilize nucleic acids under extreme conditions. We synthesized and screened 40 calcium-phosphate minerals for their ability to store and maintain the activity of lyophilized mRNA complexes. The optimal mineral formulation incorporated mRNA complexes with high efficiency (77 %), and increased mRNA transfection efficiency by 5.6-fold. Lyophilized mRNA complexes stored with the optimized mineral formulation for 6 months at 25 °C were 3.2-fold more active than those stored with state-of-the-art excipients, but without a mineral. mRNA complexes stored with minerals at room temperature did not decline in transfection efficacy from 3 days to 6 months of storage, indicating that minerals can durably maintain activity of therapeutic mRNA complexes without cold chain storage. STATEMENT OF SIGNIFICANCE: Therapeutic mRNA, such as mRNA COVID-19 vaccines, require extensive cold chain storage that limits their general application. This work screened a library of minerals to maintain the activity of mRNA complexes with freeze-drying. The optimized mineral was able to maintain mRNA activity up to 6 months of storage at room temperature outperforming current methods of freeze-drying therapeutic mRNA complexes.

Facial Feminization: Perioperative Care and Surgical Approaches.

LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Understand the regional anatomy involved in facial feminization surgery, the key differences between the male and female face, and surgical approaches for modification. 2. Appreciate the integration of preoperative virtual planning and nonoperative approaches for facial feminization care. 3. Understand the perioperative process and potential complications and sequela. 4. Understand the importance of transgender care acceptance as it pertains to clinical outcomes. SUMMARY: Facial feminization surgery (FFS) is composed of a broad spectrum of gender-affirming surgical procedures with the goal of modifying specific facial features to create a more feminine appearance. As FFS continues to evolve as a subspecialty of transgender care, it is important to consider the psychosocial evaluation, evolving aesthetic tastes, nonoperative facial feminization care, preoperative virtual planning, specialized instrumentation, and potential complications/sequelae when performing these procedures. Computed tomographic imaging and virtual preoperative planning may be used to assist the surgeon with morphologic typing of the brow, supraorbital rim, chin, and lateral mandible regions and aid in performing safer, more efficient procedures. The increasing number of FFS procedures performed on transwomen annually has been supported by objective outcome studies that demonstrate progress in minimizing both misgendering in social environments and reducing dysphoric feelings.

ß-catenin mRNA encapsulated in SM-102 lipid nanoparticles enhances bone formation in a murine tibia fracture repair model.

Fractures continue to be a global economic burden as there are currently no osteoanabolic drugs approved to accelerate fracture healing. In this study, we aimed to develop an osteoanabolic therapy which activates the Wnt/ß-catenin pathway, a molecular driver of endochondral ossification. We hypothesize that using an mRNA-based therapeutic encoding ß-catenin could promote cartilage to bone transformation formation by activating the canonical Wnt signaling pathway in chondrocytes. To optimize a delivery platform built on recent advancements in liposomal technologies, two FDA-approved ionizable phospholipids, DLin-MC3-DMA (MC3) and SM-102, were used to fabricate unique ionizable lipid nanoparticle (LNP) formulations and then tested for transfection efficacy both in vitro and in a murine tibia fracture model. Using firefly luciferase mRNA as a reporter gene to track and quantify transfection, SM-102 LNPs showed enhanced transfection efficacy in vitro and prolonged transfection, minimal fracture interference and no localized inflammatory response in vivo over MC3 LNPs. The generated ß-cateninGOF mRNA encapsulated in SM-102 LNPs (SM-102-ß-cateninGOF mRNA) showed bioactivity in vitro through upregulation of downstream canonical Wnt genes, axin2 and runx2. When testing SM-102-ß-cateninGOF mRNA therapeutic in a murine tibia fracture model, histomorphometric analysis showed increased bone and decreased cartilage composition with the 45 µg concentration at 2 weeks post-fracture. µCT testing confirmed that SM-102-ß-cateninGOF mRNA promoted bone formation in vivo, revealing significantly more bone volume over total volume in the 45 µg group. Thus, we generated a novel mRNA-based therapeutic encoding a ß-catenin mRNA and optimized an SM-102-based LNP to maximize transfection efficacy with a localized delivery.

Magnetic and Biocompatible Polyurethane Nanofiber Biomaterial for Tissue Engineering.

Recruitment of endothelial cells to cardiovascular device surfaces could solve issues of thrombosis, neointimal hyperplasia, and restenosis. Since current targeting strategies are often nonspecific, new technologies to allow for site-specific cell localization and capture in vivo are needed. The development of cytocompatible superparamagnetic iron oxide nanoparticles has allowed for the use of magnetism for cell targeting. In this study, a magnetic polyurethane (PU)-2205 stainless steel (2205-SS) nanofibrous composite biomaterial was developed through analysis of composite sheets and application to stent-grafts. The PU nanofibers provide strength and elasticity while the 2205-SS microparticles provide ferromagnetic properties. Sheets were electrospun at mass ratios of 0-4:1 (2205-SS:PU) and stent-grafts with magnetic or nonmagnetic stents were coated at the optimal ratio of 2:1. These composite materials were characterized by microscopy, mechanical testing, a sessile drop test, magnetic field measurement, magnetic cell capture assays, and cytocompatibility after 14 days of culturing with endothelial cells. Results of this study show that an optimal ratio of 2:1 2205-SS:PU results in a hydrophobic material that balanced mechanical and magnetic properties and was cytocompatible up to 14 days. Significant cell capture required a thicker material of 0.5 mm thickness. Stent-grafts fabricated from a magnetic coating and a magnetic stent demonstrated uniform cell capture throughout the device surface. This novel biomaterial exhibits a combination of mechanical and magnetic properties that enables magnetic capture of cells and other therapeutic agents for vascular and other tissue engineering applications.

Li-Fraumeni Syndrome-Associated Dimer-Forming Mutant p53 Promotes Transactivation-Independent Mitochondrial Cell Death.

Cancer-relevant mutations in the oligomerization domain (OD) of the p53 tumor suppressor protein, unlike those in the DNA binding domain, have not been well elucidated. Here, we characterized the germline OD mutant p53(A347D), which occurs in cancer-prone Li-Fraumeni syndrome (LFS) patients. Unlike wild-type p53, mutant p53(A347D) cannot form tetramers and exists as a hyperstable dimeric protein. Further, p53(A347D) cannot bind or transactivate the majority of canonical p53 target genes. Isogenic cell lines harboring either p53(A347D) or no p53 yield comparable tumorigenic properties, yet p53(A347D) displays remarkable neomorphic activities. Cells bearing p53(A347D) possess a distinct transcriptional profile and undergo metabolic reprogramming. Further, p53(A347D) induces striking mitochondrial network aberration and associates with mitochondria to drive apoptotic cell death upon topoisomerase II inhibition in the absence of transcription. Thus, dimer-forming p53 demonstrates both loss-of-function (LOF) and gain-of-function (GOF) properties compared with the wild-type form of the protein. SIGNIFICANCE: A mutant p53 (A347D), which can only form dimers, is associated with increased cancer susceptibility in LFS individuals. We found that this mutant wields a double-edged sword, driving tumorigenesis through LOF while gaining enhanced apoptogenic activity as a new GOF, thereby yielding a potential vulnerability to select therapeutic approaches. See related commentary by Stieg et al., p. 1046. See related article by Gencel-Augusto et al., p. 1230. This article is highlighted in the In This Issue feature, p. 1027.

Coverage of genetic therapies for spinal muscular atrophy across fee-for-service Medicaid programs.

BACKGROUND: Genetic therapies are a promising treatment for children born with spinal muscular atrophy (SMA); however, their high price tags can evoke coverage restrictions. OBJECTIVE: To assess variation in coverage guidelines across fee-for-service state Medicaid programs for 2 novel genetic therapies, nusinersen and onasemnogene abeparvovec, that treat SMA. We also assessed the association of these coverage guidelines with use of the 2 genetic therapies. METHODS: We evaluated fee-for-service Medicaid coverage policies for nusinersen and onasemnogene abeparvovec from publicly available websites for the period February 2020-March 2020. We then documented areas of agreement and disagreement across 4 key coverage domains. We used 2018 and 2019 state Medicaid drug utilization data to calculate the use of nusinersen across Medicaid programs and assessed that use against the restrictiveness of the coverage guidelines. RESULTS: We identified 19 state Medicaid coverage guidelines for nusinersen. Most states agreed on diagnostics requirements; however, there were disagreements based on ventilator status. We identified 17 state Medicaid coverage guidelines for onasemnogene abeparvovec. There was more discordance in these coverage guidelines compared with nusinersen, notably in domains of SMN2 gene count and ventilator status. When comparing utilization of nusinersen with coverage restrictions, we found that the more restrictive states had considerably lower utilization of nusinersen. CONCLUSIONS: There was significant variation across fee-for-service Medicaid coverage policies for nusinersen and onasemnogene abeparvovec. Although states can impose individual coverage guidelines for each drug, we presented policy options that could reduce variation and potentially decrease the cost burden of these drugs. DISCLOSURES: This study was funded by Arnold Ventures. The authors have no conflicts of interest to disclose.

A Localized Materials-Based Strategy to Non-Virally Deliver Chondroitinase ABC mRNA Improves Hindlimb Function in a Rat Spinal Cord Injury Model.

Spinal cord injury often results in devastating consequences for those afflicted, with very few therapeutic options. A central element of spinal cord injuries is astrogliosis, which forms a glial scar that inhibits neuronal regeneration post-injury. Chondroitinase ABC (ChABC) is an enzyme capable of degrading chondroitin sulfate proteoglycan (CSPG), the predominant extracellular matrix component of the glial scar. However, poor protein stability remains a challenge in its therapeutic use. Messenger RNA (mRNA) delivery is an emerging gene therapy technology for in vivo production of difficult-to-produce therapeutic proteins. Here, mineral-coated microparticles as an efficient, non-viral mRNA delivery vehicles to produce exogenous ChABC in situ within a spinal cord lesion are used. ChABC production reduces the deposition of CSPGs in an in vitro model of astrogliosis, and direct injection of these microparticles within a glial scar forces local overexpression of ChABC and improves recovery of motor function seven weeks post-injury.

Periostin modulates extracellular matrix behavior in tendons.

Periostin, originally named osteoblast-specific factor 2 (OSF-2) has been identified primarily in collagen rich, biomechanically active tissues where its role has been implicated in mechanisms to maintain the extracellular matrix (ECM), including collagen fibrillogenesis and crosslinking. It is well documented that periostin plays a role in wound healing and scar formation after injury, in part, by promoting cell proliferation, myofibroblast differentiation, and/or collagen fibrillogenesis. Given the significance of periostin in other scar forming models, we hypothesized that periostin will influence Achilles tendon healing by modulating ECM production. Therefore, the objective of this study was to elucidate the effects of periostin during Achilles tendon healing using periostin homozygous (Postn -/-) and heterozygous (Postn +/-) mouse models. A second experiment was included to further examine the influence of periostin on collagen composition and function using intact dorsal tail tendons. Overall, Postn -/- and Postn +/- Achilles tendons exhibited impaired healing as demonstrated by delayed wound closure, increased type III collagen production, decreased cell proliferation, and reduced tensile strength. Periostin ablation also reduced tensile strength and stiffness, and altered collagen fibril distribution in the intact dorsal tail tendons. Achilles tendon outcomes support our hypothesis that periostin influences healing, while tail tendon results indicate that periostin also affects ECM morphology and behavior in mouse tendons.

Oxidative Stress and the Intersection of Oncogenic Signaling and Metabolism in Squamous Cell Carcinomas.

Squamous cell carcinomas (SCCs) arise from both stratified squamous and non-squamous epithelium of diverse anatomical sites and collectively represent one of the most frequent solid tumors, accounting for more than one million cancer deaths annually. Despite this prevalence, SCC patients have not fully benefited from recent advances in molecularly targeted therapy or immunotherapy. Rather, decades old platinum-based or radiation regimens retaining limited specificity to the unique characteristics of SCC remain first-line treatment options. Historically, a lack of a consolidated perspective on genetic aberrations driving oncogenic transformation and other such factors essential for SCC pathogenesis and intrinsic confounding cellular heterogeneity in SCC have contributed to a critical dearth in effective and specific therapies. However, emerging evidence characterizing the distinct genomic, epigenetic, and metabolic landscapes of SCC may be elucidating unifying features in a seemingly heterogeneous disease. In this review, by describing distinct metabolic alterations and genetic drivers of SCC revealed by recent studies, we aim to establish a conceptual framework for a previously unappreciated network of oncogenic signaling, redox perturbation, and metabolic reprogramming that may reveal targetable vulnerabilities at their intersection.

Cardiac Valve Bioreactor for Physiological Conditioning and Hydrodynamic Performance Assessment.

PURPOSE: Tissue engineered heart valves (TEHV) are being investigated to address the limitations of currently available valve prostheses. In order to advance a wide variety of TEHV approaches, the goal of this study was to develop a cardiac valve bioreactor system capable of conditioning living valves with a range of hydrodynamic conditions as well as capable of assessing hydrodynamic performance to ISO 5840 standards. METHODS: A bioreactor system was designed based on the Windkessel approach. Novel features including a purpose-built valve chamber and pressure feedback control were incorporated to maintain asepsis while achieving a range of hydrodynamic conditions. The system was validated by testing hydrodynamic conditions with a bioprosthesis and by operating with cell culture medium for 4 weeks and living cells for 2 weeks. RESULTS: The bioreactor system was able to produce a range of pressure and flow conditions from static to resting adult left ventricular outflow tract to pathological including hypertension. The system operated aseptically for 4 weeks and cell viability was maintained for 2 weeks. The system was also able to record the pressure and flow data needed to calculate effective orifice area and regurgitant fraction. CONCLUSIONS: We have developed a single bioreactor system that allows for step-wise conditioning protocols to be developed for each unique TEHV design as well as allows for hydrodynamic performance assessment.

p63 and SOX2 Dictate Glucose Reliance and Metabolic Vulnerabilities in Squamous Cell Carcinomas.

Squamous cell carcinoma (SCC), a malignancy arising across multiple anatomical sites, is responsible for significant cancer mortality due to insufficient therapeutic options. Here, we identify exceptional glucose reliance among SCCs dictated by hyperactive GLUT1-mediated glucose influx. Mechanistically, squamous lineage transcription factors p63 and SOX2 transactivate the intronic enhancer cluster of SLC2A1. Elevated glucose influx fuels generation of NADPH and GSH, thereby heightening the anti-oxidative capacity in SCC tumors. Systemic glucose restriction by ketogenic diet and inhibiting renal glucose reabsorption with SGLT2 inhibitor precipitate intratumoral oxidative stress and tumor growth inhibition. Furthermore, reduction of blood glucose lowers blood insulin levels, which suppresses PI3K/AKT signaling in SCC cells. Clinically, we demonstrate a robust correlation between blood glucose concentration and worse survival among SCC patients. Collectively, this study identifies the exceptional glucose reliance of SCC and suggests its candidacy as a highly vulnerable cancer type to be targeted by systemic glucose restriction.