Restoring Sulfur Homeostasis in Diabetic Wounds via SLC7A11-Mediated Cysteine Uptake: Pathophysiological Mechanisms and Surgical Applications of a Dual-Sulfur Regenerative Topical Solution Using N-Acetylcysteine and Methylsulfonylmethane

Background: Chronic diabetic wounds are characterized by persistent inflammatory arrest driven by redox collapse, mitochondrial dysfunction, and extracellular matrix (ECM) instability. Sulfur deficiency has emerged as a central upstream defect linking these pathological domains. Impaired cystine uptake via SLC7A11/xCT limits intracellular cysteine, suppresses glutathione synthesis, and destabilizes redox buffering. Oxidative stress disrupts cytoskeletal signaling, suppresses angiogenic pathways, impairs mitochondrial bioenergetics, and perpetuates chronic inflammation. Concurrent extracellular sulfur depletion compromises disulfide bonding and crosslinking in collagen, elastin, and keratin, weakening tissue mechanics and impairing cell–matrix communication.Hypothesis: A dual-sulfur regenerative approach simultaneously addresses intracellular and extracellular sulfur deficits, restoring redox balance, mitochondrial function, and ECM integrity to convert the wound microenvironment from inflammatory arrest to regenerative competence.Therapeutic Strategy: A topical formulation combining N-acetylcysteine (NAC; ~2–3% w/v) and methylsulfonylmethane (MSM; ~5–8% w/v) targets complementary compartments. NAC replenishes cysteine, restores glutathione, stabilizes mitochondria, and reprograms inflammatory pathways. MSM enhances ECM crosslinking, restores biomechanical integrity, reduces proteolytic degradation, and reactivates mechanotransduction. Application involves gentle wound cleansing, thin layer topical delivery under semi-occlusive dressing once to twice daily for 2–4 weeks, with monitoring of granulation, epithelialization, exudate, and local inflammation.Implications: Intracellular redox normalization, mitochondrial recovery, macrophage phenotype transition, angiogenic restoration, and ECM stabilization converge to initiate coordinated tissue regeneration. Sulfur homeostasis thus serves as a unifying upstream regulator and therapeutic target.Conclusion: Targeting both intracellular and extracellular sulfur deficits provides a rational, mechanism-driven strategy to accelerate wound closure, restore tissue quality, and enhance vascular stability. This dual-sulfur approach redefines the biological potential of diabetic wound therapy.