Pulsed Electromagnetic Fields and Tumor-Targeted Radiofrequencies in Cancer Therapy: A Review of Experimental and Clinical Evidence

 

Targeting 15-PGDH for Drug Development

 

Hung V. Le

Biologics & Drug Targets, ProSci LLC, Rockaway, The United States

ORCID

https://orcid.org/0000-0002-6913-2373 (Hung Van Le)

 

02/10/2026

 

Abstract

 

15-Hydroxyprostaglandin dehydrogenase (15-PGDH), encoded by HPGD, is the principal enzyme responsible for the metabolic inactivation of prostaglandin E₂ (PGE₂), a lipid mediator with central roles in inflammation, tissue repair, stem cell function, and cancer biology. By constraining PGE₂ signaling, 15-PGDH functions as a dominant endogenous brake on regeneration. Across multiple tissues, aging and injury are associated with increased 15-PGDH activity, leading to impaired repair capacity. Recent preclinical studies demonstrate that pharmacologic inhibition of 15-PGDH restores physiologic PGE₂ signaling and robustly enhances regeneration in skeletal muscle, neuromuscular junctions, cartilage, hematopoietic stem cell niches, and the neurovascular unit. In contrast, extensive cancer biology literature establishes 15-PGDH as a bona fide tumor suppressor that is frequently silenced in malignancy, where loss of enzymatic activity promotes tumor growth, angiogenesis, immune evasion, and metastasis. This duality presents both opportunity and challenge for drug development. This review synthesizes emerging biological and translational evidence supporting both inhibition and restoration of 15-PGDH, evaluates the current clinical and preclinical landscape, and examines safety considerations centered on oncogenic risk. We argue that successful therapeutic targeting of 15-PGDH will depend on context-specific strategies that optimize therapeutic index through temporal limitation, spatial restriction, biomarker-guided dosing, and careful patient selection.

 

1. Introduction

15-Hydroxyprostaglandin dehydrogenase (15-PGDH, encoded by HPGD) is the principal enzyme responsible for the metabolic inactivation of prostaglandin E₂ (PGE₂) and related lipid mediators. By catalyzing the NAD⁺-dependent oxidation of PGE₂ to inactive 15-keto-PGE₂, 15-PGDH functions as a critical “brake” on prostaglandin signaling. PGE₂, acting through EP receptors (EP1–EP4), exerts pleiotropic effects on inflammation, stem and progenitor cell function, tissue repair, vascular integrity, and cell survival.

Across multiple tissues, aging and injury are associated with pathological upregulation of 15-PGDH, resulting in diminished local PGE₂ signaling and impaired regenerative responses. Pharmacologic or genetic inhibition of 15-PGDH therefore represents a strategy to restore endogenous repair programs (1-7), rather than introducing exogenous growth factors or cell therapies. This concept underlies the recent surge of interest in 15-PGDH inhibitors such as SW033291, SW209415, and MF-300 (8-10).

However, PGE₂ is also a well-established pro-tumorigenic mediator, promoting proliferation, angiogenesis, immune evasion, and metastasis (11). In many cancers, HPGD expression is epigenetically silenced, and restoration of 15-PGDH suppresses tumor growth. Thus, 15-PGDH occupies a biologically paradoxical position: a regeneration brake in aging and injury, but a tumor suppressor in cancer. Any therapeutic strategy targeting this enzyme for inhibition must therefore hinge on achieving a favorable therapeutic index that maximizes benefit in degenerative or acute injury settings while minimizing long-term oncogenic risk. Conversely, strategy that aims to restore 15-PGDH expression and activity to achieve an anti-tumor effect must consider its degenerative side effects in normal tissues.

Figure 1. Context-dependent roles of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in regeneration and tumor suppression. 15-Hydroxyprostaglandin dehydrogenase (15-PGDH), encoded by HPGD, catalyzes the irreversible inactivation of prostaglandin E₂ (PGE₂) and functions as a metabolic gatekeeper of EP receptor signaling. Center, 15-PGDH determines local PGE₂ availability and signaling amplitude. Top, in aging and tissue injury, elevated 15-PGDH activity reduces PGE₂ below a functional threshold, impairing regeneration in skeletal muscle, neuromuscular junctions, cartilage, hematopoietic stem cell niches, and the neurovascular unit. Transient or spatially restricted inhibition of 15-PGDH restores physiologic PGE₂ signaling and re-engages endogenous repair programs. Bottom, in cancer, 15-PGDH acts as a tumor suppressor and is frequently silenced through epigenetic, oncogenic, and microRNA-mediated mechanisms, resulting in PGE₂ accumulation that promotes proliferation, angiogenesis, immune evasion, and metastasis. Restoration of 15-PGDH activity suppresses these tumor-promoting processes.

2. 15-PGDH across disease indications

2.1 Muscle and Neuromuscular Regeneration

A convergent body of work identifies prostaglandin E₂ (PGE₂) as a central, physiologic regulator of skeletal muscle and neuromuscular regeneration, with the prostaglandin-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) acting as a key negative checkpoint. In young, injured muscle, transient PGE₂ signaling is required for efficient repair, whereas in aging and denervation, aberrant accumulation of 15-PGDH lowers PGE₂ below a functional threshold, impairing regenerative capacity. Pharmacologic or genetic inhibition of 15-PGDH restores PGE₂ to youthful levels, re-engaging endogenous repair programs.

At the level of skeletal muscle, PGE₂ directly targets muscle stem cells (MuSCs) through EP4 receptor signaling to drive rapid cell-cycle entry and clonal expansion during the early inflammatory phase of regeneration. Acute enhancement of PGE₂ signaling is sufficient to markedly augment muscle repair and recovery of strength, whereas suppression of prostaglandin synthesis (for example, by NSAIDs) compromises these processes (1). In aging, skeletal muscle exhibits a pronounced increase in 15-PGDH expression and activity, derived from both myofibers and tissue-resident macrophages, resulting in reduced PGE₂ availability. Short-term inhibition of 15-PGDH in aged mice reverses key features of sarcopenia, including reduced myofiber cross-sectional area, loss of muscle mass, and diminished contractile force. These effects are causally linked to PGE₂ restoration, as ectopic overexpression of 15-PGDH in young muscle is sufficient to induce rapid atrophy and weakness.

Mechanistically, restoration of PGE₂ signaling through 15-PGDH inhibition orchestrates coordinated remodeling of aged muscle tissue. This includes suppression of transforming growth factor-β and ubiquitin–proteasome–mediated atrophy pathways, alongside enhanced autophagy flux and mitochondrial biogenesis with normalization of mitochondrial ultrastructure. The convergence of these pathways explains how modest, physiologic increases in PGE₂ can yield disproportionately large functional gains, distinguishing 15-PGDH inhibition from purely anabolic or anti-catabolic strategies (2).

More recent work extends the relevance of 15-PGDH beyond muscle-intrinsic regeneration to neuromuscular connectivity. Denervation, whether acute after nerve injury or chronic during aging, induces robust expression of 15-PGDH in myofibers, particularly in fast-twitch fibers that are preferentially lost in sarcopenia and neuromuscular disease. Inhibition of 15-PGDH accelerates motor axon regeneration, restores neuromuscular junction (NMJ) structure, and improves force recovery after peripheral nerve injury. In aged animals with chronic denervation, 15-PGDH inhibition increases motor neuron viability and re-establishes functional NMJs. Importantly, restored PGE₂ signaling activates cAMP–CREB pathways not only in muscle but also in motor neurons, indicating coordinated pre- and postsynaptic regeneration (3).

Taken together, these findings position 15-PGDH as a central, druggable regulator of muscle mass, strength, and neuromuscular integrity. Inhibition of this enzyme offers a unified therapeutic strategy for sarcopenia of aging, traumatic muscle and nerve injuries, and neuromuscular or muscular dystrophies characterized by denervation and impaired regeneration. By restoring endogenous PGE₂ signaling to physiologic levels, 15-PGDH inhibitors engage intrinsic repair mechanisms across the muscle–nerve unit, supporting their broader consideration as regenerative therapeutics across multiple indications.

2.2 Osteoarthritis and cartilage regeneration

Singla et al. (4) demonstrate that 15-PGDH expression is increased in articular cartilage of aged and injured joints, particularly within hypertrophic-like chondrocyte populations. Both systemic and intra-articular inhibition of 15-PGDH with SW033291 led to robust regeneration of hyaline cartilage, reduced osteoarthritic pathology, and decreased pain behaviors in murine models.

Single-cell RNA-seq and multiplexed imaging revealed a key mechanistic insight: cartilage regeneration did not arise from stem or progenitor cell expansion, but rather from phenotypic reprogramming of existing chondrocytes. SW033291 reduced hypertrophic, degenerative chondrocyte subsets and expanded extracellular-matrix-producing articular chondrocytes. This distinguishes 15-PGDH inhibition from many regenerative approaches that rely on proliferation, suggesting a potentially lower oncogenic burden within cartilage itself.

Importantly, both local and short-term systemic inhibition were sufficient to achieve benefit, highlighting the feasibility of spatially restricted or temporally limited dosing, a key consideration for safety.

2.3 Hematopoietic aging and stem cell regeneration

Chaudhary et al. (5) extend earlier work showing that 15-PGDH constrains hematopoietic stem cell (HSC) function by degrading PGE₂. In aged mice, 15-PGDH expression and enzymatic activity remain conserved in bone marrow and spleen, making it a viable target even late in life. Prolonged pharmacologic inhibition increased the number and functional capacity of HSCs and progenitors, improved engraftment after transplantation, accelerated multilineage reconstitution, and mitigated age-associated myeloid bias.

A crucial observation is that 15-PGDH inhibition by SW033291 did not perturb steady-state hematopoiesis, but selectively enhanced regeneration under stress (e.g., transplantation). This context dependence suggests that 15-PGDH inhibition amplifies endogenous repair signals rather than inducing uncontrolled proliferation. Nonetheless, because hematopoietic tissues are intrinsically susceptible to malignant transformation, this indication sits close to the boundary where regenerative benefit and cancer risk intersect. Short peri-transplant courses (IV or parenteral) that boost HSC engraftment are an appealing clinical use because they are time-limited and target a high-value, high-risk clinical need (older transplant recipients).

2.4 Alzheimer’s disease and traumatic brain injury: Blood-Brain Barrier-centric neuroprotection

Koh et al. (6) identify a novel role for 15-PGDH in the brain, localized predominantly to microglia and perivascular macrophages associated with the blood-brain barrier (BBB). In human and murine Alzheimer’s disease (AD), traumatic brain injury (TBI), and aging, 15-PGDH expression and activity are markedly elevated. This elevation correlates with oxidative stress, BBB breakdown, neuroinflammation, and cognitive decline.

Pharmacologic inhibition or genetic reduction of 15-PGDH preserved BBB integrity, suppressed reactive oxygen species, reduced neurodegeneration, and most strikingly fully preserved cognitive function in mouse models of AD and TBI. Notably, these effects occurred without altering amyloid pathology, positioning 15-PGDH inhibition as a non-amyloid, vascular/immune mechanism of neuroprotection.

The localization of 15-PGDH to BBB-associated myeloid cells suggests that targeted modulation of inflammatory lipid metabolism underlies the benefit. This cellular specificity again raises the possibility of achieving efficacy with limited systemic exposure. However, brain indications often require chronic or repeated dosing, which reopens the long-term cancer question unless dosing can be restricted or targeted (e.g., CNS-penetrant agents given episodically).

2.5 Ischemic stroke and ferroptosis suppression

Xu et al. (7) provide a mechanistically detailed account of 15-PGDH in acute ischemic stroke. Overexpression of 15-PGDH exacerbated infarct size, edema, neurological deficits, and neuronal death, whereas inhibition with SW033291 was strongly neuroprotective in both in vivo rat middle cerebral artery occlusion (MCAO) models and in vitro oxygen glucose deprivation/reperfusion (OGD/R) neuronal cultures.

The key mechanistic advance is the linkage of 15-PGDH to ferroptosis, an iron-dependent, lipid peroxidation-driven form of regulated cell death. 15-PGDH inhibition activated the PGE₂/EP4 axis, leading to c-AMP responsive element-binding protein (CREB)- and NF-κB-dependent transcriptional upregulation of glutathione peroxidase 4 (GPX4), the central suppressor of ferroptosis. Genetic ablation of GPX4 abolished the protective effect of PGDH inhibition, establishing a causal pathway.

This work positions 15-PGDH inhibition as an acute neuroprotective strategy with a defined molecular endpoint (GPX4 restoration), well suited to short-duration intervention, arguably the safest therapeutic context for a target with oncogenic liabilities.

2.6 Cancer and tumor microenvironment: the countervailing evidence

The comprehensive review by Tulimilli et al. (11) synthesizes decades of evidence identifying 15-PGDH as a bona fide tumor suppressor across colorectal, breast, gastric, lung, pancreatic, hepatic, and other cancers . In most malignancies, 15-PGDH expression is reduced via methylation of CpG islands in the promoter region, histone deacetylation in association with transcription repressors, microRNA regulation (e.g. miR-620 in breast and prostate cancer, miR-155 in esophageal cancer), inflammatory cytokines (e.g., IL-1β, TNF-α), and oncogenic signaling pathways (EGFR, β-catenin, Snail/Slug).

Loss of 15-PGDH leads to PGE₂ accumulation, which drives proliferation, angiogenesis, immune evasion, and resistance to apoptosis. Conversely, restoring 15-PGDH expression suppresses tumor growth, induces apoptosis and cell-cycle arrest, and reduces metastasis in multiple in vitro and in vivo models. These data establish cancer predisposition as a credible, mechanism-based risk of chronic or systemic 15-PGDH inhibition.

Table 1. Summary of 15-PGDH Inhibition Studies Across Disease Models

Disease / Indication	Model System	Inhibitor Used	Dosing Regimen (systemic/local, duration)	Primary Outcomes	Mechanistic Insights	Clinical Translation Status
Skeletal muscle regeneration / Sarcopenia	Young and aged mice; muscle injury models	SW033291	Systemic (oral or parenteral); short-term and subchronic	Increased muscle mass, fiber cross-sectional area, and contractile force; reversal of sarcopenia phenotypes	Restoration of PGE₂–EP4 signaling in muscle stem cells; suppression of TGF-β and proteasome-mediated atrophy; improved autophagy and mitochondrial function	Phase 1 completed for oral inhibitor (MF-300); Phase 2 planned
Neuromuscular junction degeneration / Denervation	Acute and chronic denervation in mice; nerve injury models	SW033291	Systemic; short-term	Accelerated motor axon regeneration; restoration of NMJ structure; improved force recovery	PGE₂-driven cAMP–CREB signaling in both muscle fibers and motor neurons; coordinated pre- and postsynaptic regeneration	Preclinical
Osteoarthritis / Cartilage degeneration	Murine post-traumatic and age-related OA models	SW033291	Systemic or intra-articular; short-term	Regeneration of hyaline cartilage; reduced OA pathology and pain behaviors	Phenotypic reprogramming of chondrocytes; reduction of hypertrophic/degenerative subsets without stem cell expansion	Preclinical
Hematopoietic aging / Bone marrow transplantation	Aged mice; bone marrow transplant models	SW033291; (+)-SW209415	Systemic; short peri-transplant dosing (IV-capable for SW209415)	Increased HSC number and function; improved engraftment and multilineage reconstitution	Amplification of stress-induced PGE₂ signaling without perturbing steady-state hematopoiesis	Preclinical; strong translational rationale for peri-transplant use
Alzheimer’s disease	Transgenic AD mouse models; aging models	SW033291	Systemic; subchronic	Preservation of cognitive function; reduced neurodegeneration; preserved BBB integrity	Inhibition of microglial/perivascular 15-PGDH; reduced oxidative stress and neuroinflammation; BBB-centric protection	Preclinical
Traumatic brain injury (TBI)	Murine TBI models	SW033291	Systemic; acute to subchronic	Reduced neuronal loss; preserved cognitive and neurological function	PGE₂-mediated protection of BBB and suppression of reactive oxygen species	Preclinical
Ischemic stroke	Rat MCAO models; neuronal OGD/R cultures	SW033291	Systemic; acute	Reduced infarct size, edema, and neurological deficits	Activation of PGE₂–EP4–CREB/NF-κB signaling; upregulation of GPX4; suppression of ferroptosis	Preclinical; well suited for short-duration intervention
Sarcopenia (clinical development)	Healthy volunteers (Phase 1)	MF-300	Oral, systemic; single and multiple ascending doses	Favorable PK/PD; evidence of target engagement	Systemic inhibition of 15-PGDH with modulation of PGE₂ metabolites	Phase 1 completed; Phase 2 planned

3. Clinical-translation landscape: MF-300, SW033291, (+)-SW209415

MF-300 (Epirium Bio): an oral 15-PGDH inhibitor (Phase-1 completed)

MF-300 has completed first-in-human single and multiple ascending dose clinical trial. Publicly available report of this Phase-1 study indicate tolerability, dose-dependent pharmacokinetic (PK), and pharmacodynamic (PD) evidence of target engagement (changes in PGE₂ metabolites and other mechanistic biomarkers). Epirium is advancing MF-300 into Phase-2 development for sarcopenia (10).

This is the first publicly reported human evidence that systemic 15-PGDH inhibition can deliver pharmacological effects in humans with acceptable acute tolerability, an important “feasibility” milestone. For chronic indications (sarcopenia), MF-300 shows promise mechanistically but demands a long-term safety and cancer-surveillance strategy in later trials.

SW033291 (Case Western / academic program): a 15-PGDH inhibitor for pre-clinical studies

SW033291 is the prototypical small-molecule 15-PGDH inhibitor used across multiple published preclinical studies: hematopoietic regeneration, colon/colitis models, bone/muscle repair, and more recently in AD/TBI/stroke neuroscience studies (8). Most studies rely heavily on SW033291 for in vivo pharmacology.

SW033291 has a deep preclinical track record and has been used in investigator-led translational work (Case Western). If moved into humans, its profile supports both acute (IV/peri-transplant) and subchronic (oral/other) use cases, but clinical trial registration details have not been reported.

(+)-SW209415: a water-soluble, IV-capable second-generation analogue

Medicinal-chemistry work produced (+)-SW209415 (a racemate) with orders-of-magnitude improved aqueous solubility while retaining potency. This enables IV dosing for peri-operative or transplant use where short IV infusions could be given in a tightly controlled temporal window. Preclinical bone marrow transplantatio (BMT) models and other regeneration models show strong efficacy (9).

SW209415 (IV) directly addresses the therapeutic-index problem for hematopoietic/transplant use by enabling short, high-impact dosing windows rather than chronic systemic exposure.

4. Safety, cancer risk, and the therapeutic-index problem

In most cancers and preclinical tumor models, low 15-PGDH and high PGE₂ are associated with tumor initiation, progression, angiogenesis, and immune suppression. Restoring 15-PGDH is tumor-suppressive; conversely, sustained inhibition would raise PGE₂ and could accelerate latent premalignant clones or worsen tumor microenvironments. Successful development of a clinical candidate based on 15-PGDH inhibition depends on optimizing factors that could improve the therapeutic index for the indication of interest (Figure. 2).

These factors could include limiting the duration of intervention. For example, short pulses as in peri-transplant or acute stroke/TBI, minimize cumulative PGE₂ exposure and therefore cancer-promotion risk. The SW209415 IV program is prototypical of this approach. Localized administration, as in intra-articular or topical administration for osteoarthritis, concentrates drug in the joint and lowers systemic exposure (1). Rigorous patient selection and monitoring could minimize baseline risk. Excluding or closely monitoring patients with high cancer risk or known premalignant lesions will reduce the near-term oncologic hazard. Dosing  guided by biomarkers (urinary/tissue PGE₂ metabolite) could help determine minimal effective dose (7).

MF-300 Phase-1 shows acute tolerability and favorable pharmacodynamic, lowering a key pharmacologic uncertainty in humans. However, it does not prove long-term safety (oncologic risk requires longer observation). Similarly, preclinical SW033291 / SW209415 data support efficacy and suggest short schedules are effective and therefore safer from an oncogenic perspective.

Table 2. Countervailing Evidence and Safety Considerations for Targeting 15-PGDH

Context	Evidence Source	Role of 15-PGDH	Key Findings	Implications for Therapy	Risk Mitigation Strategies
Solid tumors (multiple types: colorectal, breast, lung, gastric, pancreatic, hepatic)	Human tumor samples; cell lines; mouse xenograft models	Tumor suppressor	15-PGDH frequently silenced via epigenetic repression, oncogenic signaling, and microRNAs; loss leads to elevated PGE₂	Chronic or systemic 15-PGDH inhibition may promote tumor growth, angiogenesis, immune evasion, and metastasis	Avoid chronic systemic dosing; exclude high-risk patients; long-term cancer surveillance
Tumor microenvironment (TME)	Preclinical cancer models	Regulator of inflammatory lipid signaling	Reduced 15-PGDH increases PGE₂-EP signaling, suppressing antitumor immunity and promoting pro-tumor macrophage phenotypes	Inhibition may worsen immune suppression within the TME	Restrict inhibition to non-oncologic indications; limit exposure duration
Epigenetic regulation in cancer	Human tumors; mechanistic studies	Transcriptionally repressed	Promoter methylation, HDAC recruitment, and EMT factors (Snail/Slug) suppress HPGD expression	Restoring 15-PGDH is a rational anticancer strategy	Tumor-targeted epigenetic modulation; localized delivery
MicroRNA-mediated repression	Cancer cell studies	Post-transcriptional target	Oncogenic miRNAs (e.g., miR-21, miR-155) reduce 15-PGDH mRNA stability	Supports reactivation strategies but cautions against inhibition	Tumor-specific antagomirs or nanoparticle delivery
Regeneration vs oncogenesis trade-off	Comparative analysis across indications	Context-dependent metabolic brake	PGE₂ promotes regeneration in normal tissues but tumor progression in cancer	Therapeutic index is highly indication-specific	Temporal limitation (acute dosing), spatial restriction (local/IV), biomarker-guided dosing
Hematopoietic system	Aging and transplant models	Constraint on stress hematopoiesis	Inhibition enhances regeneration under stress but not steady state	Hematologic malignancy risk must be considered	Short peri-transplant dosing; avoid chronic exposure
CNS indications (AD, TBI, stroke)	Preclinical models	BBB-associated regulator	Inhibition preserves BBB and neuronal viability without altering amyloid	Chronic CNS dosing may carry latent oncogenic risk	Episodic or acute treatment paradigms; CNS-targeted delivery
Cancer therapy (reactivation strategies)	Preclinical cancer models	Therapeutic target	Restoring 15-PGDH suppresses tumor growth and metastasis	Represents opposite but complementary therapeutic direction	Combine with COX-2/mPGES-1 or EP receptor blockade; patient selection via PGE₂/HPGD biomarkers

Figure 2. Optimizing therapeutic index. The opposing biological consequences of 15-PGDH modulation define a therapeutic-index problem. Successful clinical targeting of 15-PGDH—either by inhibition for regenerative indications or by restoration for cancer therapy—will require context-specific strategies that optimize benefit while minimizing risk through temporal limitation, spatial restriction, biomarker-guided dosing, and careful patient selection.

5. 15-PGDH reactivation as a cancer treatment modality?

Tulimilli, S.V. et al. (11) present a comprehensive picture of 15-hydroxyprostaglandin dehydrogenase (15-PGDH, encoded by HPGD) as a central node where inflammation, prostaglandin metabolism, and tumor biology intersect. In normal physiology, 15-PGDH serves as the principal catabolic enzyme for prostaglandin E₂ (PGE₂), converting it to inactive metabolites and thereby restraining the spectrum of PGE₂-driven signaling: proliferation, angiogenesis, immune modulation, and matrix remodeling. In many tumor types, however, this restraint is lost. The review synthesizes evidence from multiple cancers showing that HPGD expression is frequently suppressed and that this suppression is functionally important for tumor progression because it permits persistent, high local PGE₂ levels that favor malignant phenotypes.

A key strength of the review is its emphasis on the multi-layered mechanisms by which cancers reduce 15-PGDH. Rather than a single on/off switch, repression occurs through convergent transcriptional, epigenetic, post-transcriptional and microenvironmental routes. Promoter CpG hypermethylation and recruitment of chromatin-repressive complexes (including HDACs) are repeatedly documented across tumor types and provide a durable block to transcription. On top of that, several oncogenic signaling programs, Wnt/β-catenin, EGFR/MAPK, and epithelial-to-mesenchymal transcription factors such as Snail and Slug, actively repress HPGD transcription. The tumor microenvironment amplifies repression: proinflammatory cytokines (IL-1β, TNF-α) and oxidative stress further suppress expression or activity. At the post-transcriptional level, a cohort of oncogenic microRNAs (e.g., miR-21, miR-155 and others cataloged in the review) target HPGD mRNA, reducing stability or translation and yielding multilayered, robust downregulation. The net effect is a tumor milieu that both makes and preserves high PGE₂.

This mechanistic heterogeneity matters for pharmacology: it suggests multiple, rational levers to restore 15-PGDH activity, and the possibility for several translational approaches. Classic epigenetic drugs, DNA methyltransferase (DNMT) inhibitors and histone deacetylase (HDAC) inhibitors, can relieve promoter methylation and chromatin compaction and thereby re-enable transcription; these agents have the advantage of clinical availability but suffer from broad, nonselective genomic effects that can activate undesired genes and cause systemic toxicity. Targeting upstream signaling is another option: inhibitors of EGFR/MEK or modulators of Wnt signaling may indirectly derepress HPGD in tumors where those pathways dominate. MicroRNA antagonists (antagomirs) offer sequence specificity and could selectively restore HPGD post-transcriptionally, particularly if delivered locally or within tumor-targeted nanoparticles. Tulimilli, S.V. et al. (11) highlights gene-delivery approaches, viral or nanoparticle vectors expressing HPGD, which bypass endogenous repression and have shown tumor-suppressive effects in preclinical models. Finally, combination strategies that pair HPGD reactivation with other modalities, including blocking PGE₂ synthesis (COX-2/mPGES-1 inhibitors) and receptor binding (12), or anti-angiogenic agents are conceptually attractive because they both reduce PGE₂ production and accelerate its catabolism.

The review makes several persuasive points for pursuing 15-PGDH as a cancer drug target. Restoring 15-PGDH consistently reduces tumor cell proliferation, invasiveness, and colony formation across multiple models; it curtails angiogenesis and can reprogram the tumor microenvironment away from an immunosuppressive, repair-favoring state. These effects are mechanistically coherent because PGE₂ acts on EP receptors to promote proliferation, survival and immune evasion; removing PGE₂ by enhanced catabolism should therefore reverse those signals. Moreover, HPGD status offers a potential biomarker: tumors with epigenetic silencing of HPGD and high COX-2/PGE₂ signatures may be most dependent on PGE₂ and thus most likely to respond to reactivation strategies. The availability of multiple modality options, epigenetic drugs, pathway inhibitors, miRNA tools, and gene therapy—makes HPGD a practical target for translational programs.

Those upsides are tempered, properly, by the risks and caveats that Tulimilli, S.V. et al. (11) emphasizes. Because 15-PGDH is the main catabolic brake on PGE₂, systemic or chronic up-regulation of the enzyme will lower PGE₂ systemically and can blunt physiological PGE₂ roles in tissue repair and homeostasis. PGE₂ has established, context-dependent pro-regenerative effects in bone, muscle, hematopoietic stem cell niches, and in ischemic tissues; lowering PGE₂ in these contexts could delay wound healing, impair fracture repair, suppress stem/progenitor cell function, and reduce protective inflammatory resolution. The review therefore argues for therapeutic strategies that preserve the antitumor benefit while limiting deleterious systemic reductions in pro-regenerative prostaglandin signaling.

From a translational standpoint synthesis of the available data points to several practical principles. First, localization matters: intratumoral or organ-targeted delivery of HPGD reactivation (gene delivery, local antagomirs, tumor-targeted nanoparticles) reduces systemic exposure and thus spares regenerative physiology elsewhere. Second, temporal control, short pulses timed around cytotoxic therapy or perioperative windows, may permit tumoral suppression without long-term impairment of repair. Third, combination approaches that both limit PGE₂ synthesis (COX-2/mPGES blockade) and restore catabolism may permit lower doses and mitigate compensatory feedback. Fourth, patient selection using HPGD/COX-2/PGE₂ signatures and exclusion of patients with high risk of wound-healing complications or ischemic vulnerability could focus benefit where the therapeutic index is favorable.

Finally, the available information on 15-PGDH as tumor suppressor underscores the need for an evidence-driven research agenda. Preclinical models must include rigorous assessments of regeneration and repair endpoints (wound healing, bone/cartilage repair, hematopoietic recovery, and neurovascular resilience) alongside antitumor efficacy. Biomarkers that report both tumor PGE₂ activity and systemic prostaglandin levels will be essential to establish safe dosing regimens. And mechanistic work to identify tumor contexts where HPGD reactivation is most likely to yield durable responses (for example, tumors with epigenetic HPGD silencing and high PGE₂ dependence) will increase the chance of a favorable clinical outcome. In sum, Tulimilli, S.V. et al. (11) present 15-PGDH not as a simple oncoprotein or tumor suppressor but as a druggable metabolic node whose therapeutic value will depend on careful engineering of modality, timing, and patient selection to exploit tumor vulnerability while avoiding impairment of normal tissue regeneration.

6. Current translational landscape for 15-PGDH restoration in cancer

As discussed previously, multiple direct approaches ranging from gene therapy, targeting epigenetic silencing and microRNAs , and small molecules activators, could be undertaken to restore 15-PGDH activity in cancer cells. Unfortunately, most translational studies to date remain at the experimental pre-clinical level (13-16). Only indirect studies of 15-PGDH upregulation by Vitamin D have reached clinical trials stage for chemoprevention of cancer.

Vitamin D upregulates 15-PGDH primarily through a genomic mechanism involving the Vitamin D Receptor (VDR). By acting as a ligand-activated transcription factor, the active form of Vitamin D (calcitriol) directly increases the production of the 15-PGDH enzyme at the mRNA level. Vitamin D supplemented with calcium is known to exert a "metabolic sandwich" effect to aggressively lower PGE₂ levels. It not only upregulates 15-PGDH but also downregulates COX2 and EP2 receptor (17-21).

To date the clinical studies showed no effect on cancer incidence in the general population although lower incidence could be demonstrated in some subgroups including individuals with normal body mass index (BMI), and potentially African Americans. These studies also showed a small reduction in cancer mortality in the treated group (22,23 ), providing the impetus for employing a more selective 15-PGDH reactivator to avoid the potential confounding effect of Vitamin D, which is highly pleiotropic affecting multiple metabolic pathways (24).

7. Conclusion

15-hydroxyprostaglandin dehydrogenase (15-PGDH) occupies a uniquely complex position at the intersection of regeneration, inflammation, aging, and cancer biology. Across diverse tissues, accumulated preclinical and emerging clinical evidence establishes 15-PGDH as a dominant endogenous brake on prostaglandin E₂ (PGE₂)–dependent repair programs. Inhibition of this enzyme restores physiologic PGE₂ signaling and reproducibly enhances regeneration in skeletal muscle, neuromuscular junctions, cartilage, hematopoietic stem cell niches, and neurovascular units. These effects are achieved not by supraphysiologic stimulation, but by reactivating latent, evolutionarily conserved repair pathways that decline with age or injury.

At the same time, decades of cancer biology research demonstrate that loss of 15-PGDH is a hallmark of tumor progression in multiple malignancies, positioning the enzyme as a bona fide tumor suppressor. This duality defines both the promise and the challenge of therapeutically targeting 15-PGDH. Sustained or systemic inhibition carries a credible, mechanism-based oncogenic risk, while restoration or activation of 15-PGDH represents a rational anticancer strategy with its own potential liabilities related to impaired tissue repair.

The translational path forward therefore hinges on therapeutic-index engineering rather than binary target validation. For 15-PGDH inhibition, the strongest near-term opportunities lie in indications that permit temporal or spatial restriction of drug exposure, including acute injury (stroke, TBI), peri-transplant hematopoietic regeneration, localized osteoarthritis, and possibly episodic treatment paradigms for sarcopenia. The development of agents such as MF-300, and IV-capable analogues like SW209415, demonstrates that pharmacologic modulation of 15-PGDH is feasible in humans and that short-duration or localized dosing strategies are realistic.

Conversely, efforts to restore or augment 15-PGDH activity in cancer highlight a complementary therapeutic direction. Epigenetic reactivation, microRNA targeting, gene-delivery strategies, and combination approaches that simultaneously suppress PGE₂ synthesis and enhance catabolism all represent viable avenues for clinical exploration. In this context, careful patient selection based on tumor PGE₂ dependence and HPGD silencing status will be critical.

Ultimately, 15-PGDH should be viewed not as a unidirectional drug target, but as a context-dependent metabolic node whose manipulation must be tailored to disease biology, treatment duration, and delivery strategy. Future clinical success will depend on rigorous biomarker-guided dosing, long-term safety surveillance, and parallel evaluation of regenerative and oncologic outcomes. If these challenges are met, targeting 15-PGDH—either by inhibition or restoration—has the potential to inaugurate a new class of therapeutics that modulate endogenous prostaglandin metabolism to restore tissue homeostasis across aging, injury, and cancer.

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