From symptomatic relief to restorative medicine: a comprehensive review of diabetic erectile dysfunction

Introduction

Diabetes mellitus has escalated into one of the most critical public health emergencies of the 21st century, imposing a substantial burden on healthcare systems globally. According to the authoritative data from the International Diabetes Federation (IDF) Diabetes Atlas (10th edition), the global prevalence of diabetes is projected to surge from approximately 537 million adults in 2021 to an estimated 783 million by the year 2045 (1). Within this rapidly expanding demographic, erectile dysfunction (ED) stands out as a prevalent, persistent, and psychologically debilitating complication. A comprehensive systematic review and meta-analysis incorporating data from 145 studies indicated that the overall prevalence of ED in men with diabetes is as high as 52.5%. Furthermore, the onset of ED in diabetic men typically occurs 10–15 years earlier than in their non-diabetic counterparts, with a risk ratio exceeding 3.5 compared to the healthy population (2).

The burden of diabetic erectile dysfunction (DMED) is particularly pronounced in Asian populations, where rapid urbanization and lifestyle changes are driving diabetes rates. In a recent study published in Translational Andrology and Urology, Muniandy et al. investigated the prevalence and determinants of ED among men with type 2 diabetes. They highlighted that the burden of ED remains critically high, particularly in patients with comorbidities such as chronic kidney disease, necessitating proactive screening and management strategies (3). This “silent epidemic” severely compromises the quality of life, self-esteem, and intimate relationships of millions of men worldwide (Figure 1).

Figure 1 Global Burden of Diabetes and DMED. DMED, diabetic erectile dysfunction; ED, erectile dysfunction.

Since the late 1990s, the clinical management of ED has been revolutionized by the advent of phosphodiesterase type 5 inhibitors (PDE5i) such as sildenafil, tadalafil, vardenafil, and avanafil. Recent studies confirm that avanafil not only improves erectile function but also enhances systemic markers of endothelial integrity, such as nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) (4). These agents are currently endorsed as the first-line pharmacotherapy by major international guidelines, including those of the European Association of Urology (EAU). However, despite their general efficacy, their therapeutic success is significantly attenuated in the diabetic population. Recent meta-analyses and clinical observations reveal a non-response rate of approximately 40–50% among diabetic men (5). This therapeutic resistance is attributed to the complex, multifactorial pathogenesis of DMED, which involves severe endothelial injury, irreversible peripheral neuropathy, and profound endocrine dysregulation that collectively render the NO/cGMP signaling pathway ineffective (6). Crucially, ED is increasingly recognized as a robust predictor of cardiovascular disease (CVD). A 2024 systematic review and meta-analysis published in the European Heart Journal - Cardiovascular Pharmacotherapy provided compelling evidence that the chronic use of PDE5 inhibitors is associated with a significant reduction in major adverse cardiovascular events (MACE) and all-cause mortality, likely due to their systemic endothelial benefits (7).

Given these substantial limitations of current pharmacological options, there is an urgent paradigm shift occurring in the field of sexual medicine: a transition from temporary symptomatic relief towards “Restorative Therapies”. These emerging modalities aim to modify the underlying disease process, reversing pathological changes such as structural fibrosis and vascular insufficiency to restore spontaneous erectile function (8,9). This review provides a comprehensive synthesis of the “central hub” role of oxidative stress in DMED pathogenesis and critically evaluates the evidence for emerging regenerative interventions, offering a strategic algorithm for future precision medicine.

Physiological mechanisms of penile erection

Penile erection is a sophisticated neurovascular event dependent on the precise coordination between the central nervous system, peripheral nerves, and the vascular structures of the penis. Under physiological conditions, the initiation, maintenance, and detumescence of an erection rely on a dynamic and delicate balance between pro-erectile relaxant signals and anti-erectile contractile signals (10,11).

The pro-erectile pathway is triggered by sexual stimulation, which leads to the release of NO from non-adrenergic non-cholinergic (NANC) nerve terminals and the vascular endothelium. NO acts as a potent gaseous signaling molecule, rapidly diffusing into cavernous smooth muscle cells to activate the enzyme soluble guanylyl cyclase (sGC). This enzyme catalyzes the conversion of guanosine triphosphate (GTP) to the second messenger cGMP. Elevated intracellular cGMP levels subsequently activate protein kinase G (PKG). Activated PKG induces smooth muscle relaxation through multiple mechanisms, including the sequestration of intracellular calcium into the sarcoplasmic reticulum and the opening of potassium channels to cause hyperpolarization. This relaxation facilitates rapid arterial inflow, expanding the sinusoidal spaces and compressing the subtunical venules against the tunica albuginea, thereby activating the veno-occlusive mechanism to sustain penile rigidity (12).

Conversely, the flaccid state is actively maintained by the sympathetic nervous system via the release of norepinephrine (NE). NE binds to α-adrenergic receptors on smooth muscle cells, activating the RhoA/Rho-kinase (ROCK) pathway. Upon activation, ROCK phosphorylates the myosin phosphatase target subunit 1 (MYPT1), thereby inhibiting myosin light chain phosphatase (MLCP). This inhibition maintains myosin light chains in a phosphorylated state, thereby increasing calcium sensitivity and ensuring sustained smooth muscle contraction even at low intracellular calcium levels (13). In the context of diabetes, this physiological balance is fundamentally disrupted: oxidative stress depletes bioavailable NO, while hyperglycemia aberrantly upregulates the RhoA/ROCK pathway, locking the penis in a contractile, non-erectile state (Figure 2).

Figure 2 Physiological mechanisms of penile erection. AR, adrenergic receptor; cGMP, cyclic guanosine monophosphate; GTP, guanosine triphosphate; MLC, myosin light chain; MLCP, myosin light chain phosphatase; NANC, non-adrenergic non-cholinergic; NE, norepinephrine; PKG, protein kinase G; sGC, soluble guanylyl cyclase; SR, sarcoplasmic reticulum.

Pathophysiology: the pivotal role of oxidative stress

The pathophysiology of DMED is intricate, but current consensus identifies hyperglycemia-induced oxidative stress as a key instigator initiating the pathological cascade. This oxidative burden triggers a “domino effect” across vascular, neural, and endocrine systems (Figure 3).

Figure 3 Pathophysiological network linking DMED. AGEs, advanced glycation end-products; cGMP, cyclic guanosine monophosphate; CHOP, C/EBP homologous protein; DMED, diabetic erectile dysfunction; eNOS, endothelial nitric oxide synthase; EPC, endothelial progenitor cell; ER, endoplasmic reticulum; HPA, hypothalamic-pituitary-adrenal; nNOS, neuronal nitric oxide synthase; Nrf2, nuclear factor erythroid 2-related factor 2; RAGE, receptor for AGEs; ROS, reactive oxygen species; TGF-β1, transforming growth factor-β1.

The central hub: oxidative stress, AGEs, and inflammation

Long-term exposure to hyperglycemia forces mitochondrial electron transport chains to function at capacity, leading to the leakage of electrons and the supraphysiological production of superoxide anions (O₂⁻), the primary source of reactive oxygen species (ROS) (14).

NO quenching & eNOS uncoupling

The interaction between superoxide and NO is kinetically rapid, forming peroxynitrite (ONOO−), a highly cytotoxic oxidant. This reaction has a dual deleterious effect. First, it immediately depletes the bioavailability of NO required for vasodilation. Second, peroxynitrite oxidizes the zinc-thiolate cluster of eNOS and the essential cofactor tetrahydrobiopterin (BH4) into dihydrobiopterin (BH2). In the absence of sufficient BH4, eNOS undergoes a conformational change known as “uncoupling”. In this pathological state, the enzyme structurally destabilizes and transfers electrons to molecular oxygen instead of L-arginine, resulting in the paradoxical production of superoxide rather than NO. This perpetuates a vicious cycle of oxidative damage and vascular dysfunction (15).

Advanced glycation end-products (AGEs)-receptor for AGEs (RAGE) axis

Chronic hyperglycemia promotes the non-enzymatic glycation of proteins, lipids, and nucleic acids, culminating in the accumulation of AGEs. The accumulation of AGEs in cavernous tissue and their binding to the RAGE activates the nuclear factor-kappa B (NF-κB) signaling pathway. This transcriptional activation upregulates a host of proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), and interleukin-6 (IL-6), establishing a chronic low-grade inflammatory microenvironment. This inflammation is a key driver of endothelial apoptosis and cavernous fibrosis (10,16).

Pyroptosis driven by the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome

Beyond classical apoptosis, emerging research highlights the critical role of pyroptosis, a highly inflammatory form of programmed cell death, in the progression of DMED. Oxidative stress serves as a primary “danger signal” that triggers the assembly of the NLRP3 inflammasome. Upon activation by ROS, NLRP3 recruits the adaptor protein ASC and pro-caspase-1 to form a multi-protein complex, which cleaves pro-caspase-1 into its active form. Activated caspase-1 then processes the pro-inflammatory cytokines IL-1β and IL-18 into their mature forms and cleaves gasdermin D (GSDMD). The N-terminal fragment of GSDMD translocates to the cell membrane to form pores, leading to cell swelling, lysis, and the massive release of inflammatory contents. Xu et al. recently demonstrated that neutrophil extracellular traps (NETs) in diabetic tissues exacerbate this process by enhancing NLRP3-mediated pyroptosis, directly reducing the number of functional endothelial cells and creating a hostile microenvironment that prevents tissue repair (17).

Epigenetic regulation and antioxidant defense failure

Beyond direct biochemical damage, emerging evidence highlights the critical role of epigenetic modifications in the persistence of DMED, serving as the molecular basis for “metabolic memory”.

MicroRNAs (miRNAs)

Recent studies have identified that miR-155 is significantly upregulated in the cavernous tissue of diabetic rats. This upregulation targets and suppresses the expression of eNOS and preserves the inflammatory phenotype by targeting SOCS1. Conversely, protective miRNAs, such as miR-126, which maintains endothelial integrity, are downregulated in hyperglycemic environments. Restoring these protective factors via exosomal delivery has been shown to enhance angiogenesis and restore erectile function, suggesting that they are not just markers but viable therapeutic targets (18).

Failure of Nrf2/Keap1 signaling

The body possesses intrinsic defense mechanisms against oxidative stress, primarily orchestrated by nuclear factor erythroid 2-related factor 2 (Nrf2). Under physiological stress, Nrf2 activates antioxidant response elements, promoting the expression of superoxide dismutase and heme oxygenase-1 (HO-1). However, in chronic diabetes, this defense system becomes exhausted. Emerging evidence demonstrates that the Nrf2/HO-1 pathway is suppressed in diabetic cavernous tissue, leading to an unchecked accumulation of ROS and ferroptosis. Pharmacological activation of Nrf2 has been shown to re-establish redox homeostasis, inhibit ferroptosis, and preserve smooth muscle content (19).

Cellular organelle stress: endoplasmic reticulum (ER) stress and autophagy

Hyperglycemia imposes a heavy metabolic burden on the protein-folding machinery within the ER, leading to the accumulation of unfolded or misfolded proteins—a pathological state known as ER stress. To restore homeostasis, the unfolded protein response (UPR) is activated. However, under chronic diabetic conditions, the UPR becomes maladaptive. The sustained activation of stress sensors such as protein kinase R-like endoplasmic reticulum kinase (PERK) and inositol-requiring enzyme 1alpha (IRE1α) leads to the upregulation of the pro-apoptotic transcription factor C/EBP homologous protein (CHOP), which directly triggers apoptosis in cavernous smooth muscle and endothelial cells. Concurrently, diabetes disrupts autophagy, the cellular “housekeeping” process responsible for clearing damaged organelles and proteins. In a healthy state, autophagy protects cells from oxidative damage. However, in DMED, the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway is often dysregulated, inhibiting autophagy initiation. Luo et al., in a 2025 review published in the Asian Journal of Andrology, highlighted that this “autophagic block” results in the accumulation of damaged mitochondria (defective mitophagy) and ROS, further exacerbating fibrosis. Restoring autophagic flux has been proposed as a novel therapeutic strategy to alleviate ER stress and preserve erectile hemodynamics (20).

Vascular impairment: from dysfunction to remodeling

Endothelial dysfunction

The endothelium serves as the “gatekeeper” of erectile function. Oxidative stress disrupts endothelial tight junctions (e.g., zonula occludens-1), increasing vascular permeability to atherogenic macromolecules like lipoproteins. Crucially, the diabetic milieu impairs the mobilization, migration, and homing of bone marrow-derived endothelial progenitor cells (EPCs). The functional impairment and reduced number of these reparative cells severely compromise the intrinsic capacity for vascular regeneration, accelerating the progression of microangiopathy (21).

Molecular dysregulation

DMED is characterized by a “double hit” to molecular signaling. First, the suppression of the relaxant NO/cGMP pathway prevents adequate relaxation due to sGC oxidation. Second, the contractile RhoA/ROCK pathway is aberrantly upregulated. Hyperglycemia enhances the membrane translocation of active RhoA, which in turn activates ROCK. This kinase-mediated phosphorylation increases the sensitivity of the contractile apparatus to calcium, maintaining the penis in a flaccid state even in the presence of physiological stimuli (22,23). Furthermore, the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway has emerged as a key mediator of diabetic vascular injury. High glucose levels activate JAK2, which phosphorylates STAT1/3. The translocation of phosphorylated STATs to the nucleus promotes the transcription of genes encoding cell adhesion molecules (e.g., ICAM-1, VCAM-1) and pro-fibrotic factors. Xi et al. provided causal evidence using Mendelian randomization, confirming that genetically predicted JAK2 signaling is associated with an increased risk of erectile dysfunction. Aberrant JAK/STAT signaling not only perpetuates endothelial inflammation but also promotes the proliferation and migration of vascular smooth muscle cells towards a synthetic phenotype, contributing to intimal hyperplasia and structural rigidity of the cavernous arteries (24).

Structural remodeling

As the disease progresses, persistent inflammation and RhoA activation induce the overexpression of transforming growth factor-β1 (TGF-β1). This profibrotic cytokine drives the phenotypic modulation of cavernous smooth muscle cells from a functional “contractile” phenotype to a “synthetic” phenotype. This shift leads to smooth muscle atrophy and the excessive deposition of extracellular matrix components, particularly collagen types I and III. The resulting structural fibrosis reduces cavernous compliance and impairs the veno-occlusive mechanism, manifesting clinically as venous leak and failure to maintain erections (25,26).

Neural and endocrine abnormalities

Neuropathy

Diabetic neuropathy affects the autonomic cavernous nerves essential for initiating erection. Hyperglycemia activates the polyol pathway, where aldose reductase converts glucose to sorbitol. Sorbitol accumulation causes osmotic stress and depletes nicotinamide adenine dinucleotide phosphate (NADPH), reducing the synthesis of NO and glutathione. Combined with a deficiency in neurotrophic factors like nerve growth factor (NGF), this leads to axonal atrophy, demyelination, and a critical reduction in neuronal NOS (nNOS) expression, effectively severing the neural drive for erection (27).

Hypogonadism

There is a bidirectional relationship between diabetes and hypogonadism, predominantly manifesting as hypogonadotropic hypogonadism. Insulin resistance and visceral adiposity promote increased aromatase activity and suppress the hypothalamic kisspeptin neurons, leading to reduced gonadotropin-releasing hormone (GnRH) pulsatility and subsequent decreases in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion (28). Low testosterone levels are detrimental to erectile physiology, as testosterone regulates the expression of key enzymes including nNOS, eNOS, and PDE5. Thus, hypogonadism not only reduces libido but also diminishes the responsiveness to PDE5 inhibitors (29).

Central and psychological dysregulation

Recent evidence underscores the critical role of central mechanisms, forming a “bio-psycho-social” vicious cycle.

Sympathetic overdrive

Psychological distress, depression, and “performance anxiety” activate the limbic system, leading to chronic central sympathetic overdrive. In metabolic syndrome, this is not merely a symptom but a driver of pathology. Excess norepinephrine release acts on α-adrenergic receptors to hyperactivate the RhoA/ROCK pathway, physically antagonizing the relaxant effects of NO (30,31).

Neuroendocrine inhibition

Chronic stress associated with diabetes management activates the hypothalamic-pituitary-adrenal (HPA) axis. Elevated cortisol levels suppress the pulsatile secretion of GnRH, leading to secondary hypogonadism. Furthermore, neuroinflammation associated with diabetes may impair central dopaminergic circuits involved in sexual arousal and motivation (32,33).

Emerging risk factors: the gut-penis axis

Recent advances in metagenomics have unveiled a potential link between gut microbiota dysbiosis and ED, termed the “Gut-Penis Axis”. Diabetes induces significant alterations in the gut microbiome, characterized by a reduction in butyrate-producing bacteria and an increase in opportunistic pathogens. This dysbiosis leads to “leaky gut”, allowing bacterial endotoxins [lipopolysaccharide (LPS)] to enter the systemic circulation. Zhang et al. reported that fecal microbiota transplantation from healthy donors to diabetic mice significantly improved erectile function by reducing systemic inflammation and increasing cavernous nNOS expression, confirming that the gut microbiome acts as a remote modulator of erectile function (34). These multifaceted pathogenic mechanisms, ranging from organelle stress to fibrosis, underscore the need for targeted interventions. A summary of these emerging pathophysiological targets and their respective experimental therapeutics is presented in Table 1.

Comprehensive management of DMED

The clinical management of DMED is evolving from a tiered approach to a comprehensive, multimodal strategy that integrates foundational care with advanced restorative interventions (Figure 4).

Figure 4 Comprehensive management algorithm for DMED. ACE, angiotensin-converting enzyme; ADSCs, adipose-derived stem cells; DMED, diabetic erectile dysfunction; GLP-1, glucagon-like peptide-1; HbA1c, glycated hemoglobin; HUCMSCS, human umbilical cord mesenchymal stem cell; IPP, penile prosthesis implantation; Li-ESWT, low-intensity extracorporeal shockwave therapy; LIPUS, low-intensity pulsed ultrasound; nVNS, non-invasive vagus nerve stimulation; PDE5i, phosphodiesterase type 5 inhibitors; PRP, platelet-rich plasma; T2DM, type 2 diabetes mellitus; VEGF, vascular endothelial growth factor.

Foundational strategy: metabolic & lifestyle optimization

Glycemic control & metabolic memory

Strict glycemic control [glycated hemoglobin (HbA1c) <7%] is the cornerstone of management to prevent microvascular progression. However, due to the phenomenon of “metabolic memory”, early intensive control is crucial, as establishing normoglycemia later may not fully reverse established epigenetic changes in the vasculature. Concurrently, psychological screening is vital to identify and treat diabetes distress, thereby breaking the anxiety-sympathetic cycle (44).

Lifestyle & surgery

Exercise therapy is a potent tool for vascular health. Salama et al. demonstrated in a randomized controlled trial that combining aerobic and resistance training significantly improved International Index of Erectile Function-5 (IIEF-5) scores in diabetic men. The mechanism likely involves increased shear stress on the endothelium, which stimulates endogenous NO production. For patients with morbid obesity and type 2 diabetes, metabolic surgery (e.g., Roux-en-Y gastric bypass) offers profound benefits. Simonson et al., in the landmark ARMMS-T2D study, reported that metabolic surgery was superior to medical/lifestyle intervention in achieving diabetes remission and improving health-related quality of life, which translates to reduced cardiovascular risk and improved erectile function (45-47).

First-line pharmacotherapy

PDE5 inhibitors

PDE5 inhibitors (sildenafil, tadalafil, vardenafil, avanafil) remain the first-line pharmacologic therapy. However, their efficacy relies on the presence of endogenous NO to generate cGMP. In diabetic men with severe neuropathy and endothelial dysfunction, basal NO levels are insufficient, leading to a high non-response rate (40–50%). To overcome this, strategies such as daily dosing regimens or combination with antioxidants (e.g., alpha-lipoic acid) are often employed to improve endothelial function continuously (48).

Testosterone replacement therapy (TRT)

Recent guidelines and a 2024 review by Grossmann et al. emphasize that TRT should be strictly reserved for men with biochemically confirmed hypogonadism and associated clinical symptoms. In these patients, normalizing testosterone levels can upregulate NO synthase expression and salvage responsiveness to PDE5 inhibitors. Recent guidelines confirm that TRT acts synergistically with PDE5 inhibitors, significantly restoring erectile function in hypogonadal men who previously failed to respond to PDE5 inhibitor monotherapy (49). However, TRT provides no benefit for men with normal testosterone levels, highlighting the need for precision endocrine assessment (50).

Pharmacogenomics and precision dosing

The variability in patient response to PDE5 inhibitors may partly be explained by genetic polymorphisms. Recent pharmacogenomic studies suggest that single nucleotide polymorphisms (SNPs) in the guanine nucleotide-binding protein subunit GNB3 gene (e.g., C825T) are associated with better erectile responses to sildenafil, whereas polymorphisms in the ACE gene (I/D) may predict non-responsiveness. Furthermore, the bioavailability of oral PDE5 inhibitors is significantly affected by the diabetic gastroparesis often seen in long-standing diabetes. This has spurred interest in novel orodispersible film formulations, which bypass the gastrointestinal tract and offer faster onset of action. Understanding a patient’s genetic profile could allow clinicians to move from a “trial-and-error” approach to a more personalized prescription strategy, optimizing dosage and drug selection to minimize side effects and maximize efficacy (51).

Novel pharmacological agents and delivery systems

Beyond PDE5 inhibitors, newer antidiabetic agents offer potential dual benefits.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors

SGLT2 inhibitors, such as empagliflozin, are revolutionizing cardiovascular protection. Emerging preclinical evidence demonstrates that empagliflozin treatment in diabetic rats can reduce cavernosal oxidative stress and sympathetic overactivation, improving endothelial function independent of glycemic control (52).

GLP-1 receptor agonists

The widespread use of GLP-1 receptor agonists (e.g., semaglutide) raises questions about their impact on sexual function. Recent meta-analyses and clinical reviews indicate that the net effect of GLP-1 RAs on erectile function is generally positive, driven by substantial improvements in body mass index and systemic endothelial function (53). However, a more nuanced perspective is required. A recent large-scale database study by Able et al. indicated that prescribing semaglutide for weight loss is associated with a significantly increased risk of erectile dysfunction and testosterone deficiency diagnosis (54). This phenomenon may be attributed to the rapid weight loss induced by these agents.

Restorative therapies: the new frontier

Regenerative medicine aims to modify the underlying disease process rather than merely treating symptoms. It is important to note that while promising, many of these interventions are still largely investigational (8,9). These therapies target the root causes: fibrosis, vascular insufficiency, and neuropathy.

Low-intensity extracorporeal shockwave therapy (Li-ESWT)

Li-ESWT utilizes acoustic waves to create micro-trauma in penile tissue, stimulating the release of angiogenic factors such as vascular endothelial growth factor (VEGF) and recruiting endogenous stem cells (55). Caretta et al., in a pivotal study published in the Asian Journal of Andrology, utilized penile color Doppler ultrasound to demonstrate that the clinical efficacy of Li-ESWT is inversely correlated with the severity of cavernous artery disease. This finding is clinically significant as it suggests that Li-ESWT is most effective in the “window of opportunity” before irreversible vascular sclerosis occurs (56). In terms of clinical protocols, Verze et al. conducted a prospective, matched-pair analysis comparing Li-ESWT plus daily tadalafil versus tadalafil alone. At the 24-week follow-up, the combination group showed significantly higher IIEF-5 scores (P<0.05), confirming that Li-ESWT can potentiate the effects of pharmacotherapy through vascular rehabilitation (57).

Low-intensity pulsed ultrasound (LIPUS)

LIPUS is emerging as a novel non-invasive alternative to shockwave therapy. Liu et al. elucidated the molecular mechanism, demonstrating that LIPUS mechanical forces activate the mechanosensitive ion channel Piezo1. Activation of Piezo1 triggers the downstream extracellular signal-regulated kinase (ERK)-VEGF signaling axis, which significantly enhances the angiogenic capacity of adipose-derived stem cells (ADSCs) (58). Retrospective clinical data from Gao et al. indicate that LIPUS combined with tadalafil is effective even in severe ED cases (59).

Stem cell therapy: from bioengineering to cell-free strategies

To enhance therapeutic potency against the hostile diabetic microenvironment, strategies have evolved from simple cell transplantation to advanced bioengineering. Sun et al. employed a CRISPR activation (CRISPRa) system to engineer ADSCs to overexpress RXFP1, the receptor for relaxin. When transplanted into diabetic rats, these gene-modified cells exhibited superior survival rates and significantly reduced cavernous fibrosis compared to unmodified cells (60). Beyond genetic enhancement, targeting specific cell death pathways is crucial. Feng et al. identified ferroptosis—an iron-dependent form of programmed cell death—as a key mechanism of cell loss in DMED. They found that human umbilical cord mesenchymal stem cells (HUCMSCs) could preserve smooth muscle content by inhibiting ferroptosis pathways and reducing oxidative stress (61). Furthermore, expanding on the neuroprotective potential, Wang et al. reported in the Asian Journal of Andrology that HUCMSCs effectively promoted the regeneration of cavernous nerves in a rat model of injury, suggesting a dual vascular and neural protective role (62).

To overcome the inherent limitations of live cell therapy, such as immunogenicity and storage instability, research is increasingly shifting towards "cell-free" strategies using exosomes. To address the rapid "wash-out" effect seen with simple injections, contemporary bioengineering approaches have incorporated ADSC-derived exosomes into injectable thermo-sensitive hydrogels for sustained release. This localized delivery strategy has been shown to prolong therapeutic exposure, resulting in superior preservation of the endothelium and cavernous structures compared to native exosome suspensions (63).

Despite these promising preclinical results, the clinical translation of stem cell therapy faces significant hurdles. A major challenge is “anoikis” and the oxidative stress in diabetic tissue, which leads to the rapid clearance of greater than 90% of transplanted cells within 72 hours. While gene modification addresses survival, safety concerns regarding tumorigenicity remain a barrier for regulatory approval. Moreover, the lack of standardization in cell dosage, delivery routes (intracavernous vs. intravenous), and cell sources persists. Recent reviews emphasized that establishing standardized potency assays—measurable biological markers that predict clinical efficacy—is the critical next step required before stem cell therapy can become a routine clinical offering (64).

Platelet-rich plasma (PRP)

PRP is rich in growth factors, but clinical evidence remains conflicting (65). A rigorous randomized controlled trial by Masterson et al. found that although PRP improved IIEF scores numerically, the proportion of patients achieving the minimal clinically important difference (MCID) was not statistically different from the placebo group. This highlights the urgent need for standardized preparation protocols and rigorous patient selection before PRP can be broadly recommended (66).

Second-line and surgical interventions

Vacuum erection devices (VED)

For patients who fail pharmacotherapy or wish to avoid medication, VEDs offer a non-invasive solution. Beyond immediate erection, VEDs are valuable for penile rehabilitation, utilizing negative pressure to induce periodic engorgement, thereby oxygenating the tissue and preventing hypoxic fibrosis in non-responders (67). Neuromodulation and penile rehabilitation: beyond mechanical devices, novel neuromodulatory approaches are being explored to target diabetic neuropathy directly. Li-ESWT has shown neuroprotective effects, but emerging technologies like non-invasive vagus nerve stimulation (nVNS) are also being investigated for their anti-inflammatory properties via the cholinergic anti-inflammatory pathway. Preliminary data suggest that modulating autonomic tone can improve endothelial function systemically. Furthermore, the concept of “penile rehabilitation”—traditionally used after prostatectomy—is gaining traction in DMED. This involves the regular use of VEDs or daily PDE5i to induce nocturnal erections, thereby oxygenating the tissue and preventing the collagen deposition that results from chronic flaccidity (68).

Penile prosthesis implantation (IPP)

For refractory DMED, IPP remains the gold standard for restoring sexual function. Surgical techniques have evolved to improve patient outcomes. Alhefnawy et al. conducted a prospective study comparing a novel cavernous tissue preservation technique versus conventional destruction of the spongy tissue. They found that the preservation technique resulted in significantly higher patient satisfaction (83.3% vs. 70.0%) and better preservation of penile girth and residual tumescence. This underscores that even in salvage procedures, preserving physiological tissue integrity correlates with better quality of life (69).

Conclusions

DMED is a multifaceted pathology driven by a central cascade of oxidative stress that compromises vascular integrity, neural transmission, and psychological well-being. Recent discoveries regarding epigenetic memory and the gut-penis axis have further deepened our understanding of its refractory nature. The therapeutic landscape is currently undergoing a paradigm shift. While PDE5i remain the first-line symptomatic treatment, their limitations have catalyzed the development of restorative medicine. Emerging therapies, particularly Li-ESWT, gene-modified stem cells, exosomes, and novel antidiabetic agents (e.g., SGLT2 inhibitors, GLP-1 RAs), offer the promise of reversing fibrosis and restoring spontaneous function. Future research must focus on overcoming translational barriers, such as standardizing exosome isolation and optimizing delivery systems. Ultimately, a combined approach integrating metabolic optimization, psychosexual support, and restorative interventions represents the future of precision medicine for men with diabetes.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-1-945/prf

Funding: This study was supported by the Baoding Science and Technology Bureau Project (No. 2441ZF206) and the Baoding Key Laboratory for Prostate and Male Reproductive Diseases (No. 2363P007).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-1-945/coif). All authors report that this study was supported by the Baoding Science and Technology Bureau Project (No. 2442ZF206) and the Baoding Key Laboratory for Prostate and Male Reproductive Diseases (No. 2363P007). The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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