The review, written by Mohammad Amin Karimi, Pouya Mahdavi Sharif and Nima Rezaei of the Universal Scientific Education and Research Network and Tehran University of Medical Sciences, pulls together evidence from experimental models and clinical studies to argue that VAP-1 deserves a place alongside better-known players such as VEGF, PD-L1 and the integrin family in the oncology conversation. The authors were published in the journal’s open-access format on 13 August 2026, and their synthesis arrives at a moment when several VAP-1 inhibitors originally developed for inflammatory disease are being reconsidered for cancer applications. The paper’s central claim is deceptively simple: a molecule that evolved to guide immune cells through inflamed tissue can be co-opted by tumors to build the very vasculature, stroma and immunosuppressive backdrop they need to thrive.

Structurally, VAP-1 is a homodimeric, membrane-bound glycoprotein of roughly 170 kilodaltons, with a large extracellular domain that carries the copper-containing active site and the covalently bound topaquinone cofactor responsible for its enzymatic chemistry. In its adhesive role, the protein engages sialic acid-binding immunoglobulin-like lectins, particularly Siglec-9 on leukocytes, initiating the slow-rolling and firm-adhesion steps that precede transendothelial migration. The enzymatic domain, meanwhile, converts primary amines into products that can diffuse into surrounding tissue, where hydrogen peroxide acts on endothelial cells, stromal fibroblasts and infiltrating immune cells alike. A soluble form of the protein, sVAP-1, circulates in plasma and can be measured by enzyme-linked immunosorbent assay, which is where the biomarker story begins.

Clinically, the review documents a consistent pattern across tumor types. In gliomas, including glioblastoma multiforme, elevated tissue VAP-1 expression tracks with aggressive behavior and unfavorable survival, consistent with the protein’s established role in driving angiogenesis in the setting of hypoxia and vascular proliferation. In breast cancer, colorectal cancer and ovarian cancer, including high-grade serous ovarian carcinoma, the authors find that higher VAP-1 levels in tumor tissue correlate with disease progression and poorer overall survival, with the molecule implicated in stromal remodeling and metastatic seeding. In gastric and thyroid cancers, the picture is somewhat different: what matters there is the circulating concentration of soluble VAP-1, which appears to carry adjunctive diagnostic relevance when interpreted alongside conventional biomarkers, imaging findings and clinicopathological features rather than as a stand-alone test.

The mechanistic heart of the review concerns what VAP-1 actually does inside a tumor. Through its enzymatic output, hydrogen peroxide promotes a pro-angiogenic cascade that complements vascular endothelial growth factor signaling, encouraging the formation of the abnormal, leaky vasculature that characterizes many solid tumors. The same redox signaling appears to bias the immune infiltrate toward suppression. Experimental studies cited in the review describe VAP-1-dependent recruitment of CD11b-positive myeloid cells, granulocyte-marker-positive cells and myeloid-derived suppressor cells, along with a shift in tumor-associated macrophages toward the alternatively activated M2 phenotype, which is associated with tissue remodeling, angiogenesis and dampened antitumor immunity. At the same time, the T helper cell balance tilts from a cytotoxic, Th1-dominated response toward a Th2 profile that is permissive to tumor growth.

Perhaps the most clinically resonant finding is what happens when VAP-1 is blocked. In preclinical models, pharmacological inhibition of the enzymatic activity, using compounds such as PXS-4681A, PXS-4728A, U-V296 and the clinically advanced ASP8232, or antibody-based approaches such as the anti-VAP-1 monoclonal antibody timolumab, reduces angiogenesis, cuts down the infiltration of immunosuppressive myeloid cells and restores the function of CD8-positive cytotoxic T lymphocytes. Crucially, the review highlights synergy when VAP-1 inhibition is combined with immune checkpoint inhibitors, the class of drugs that includes antibodies against PD-1, PD-L1 and CTLA-4. The rationale is straightforward: checkpoint blockade unleashes T cells that are already present, but if the tumor microenvironment is physically and chemically hostile to T cell infiltration in the first place, the drugs cannot work. VAP-1 inhibition appears to open the door, allowing checkpoint inhibitors to act on a more responsive immune landscape.

This framing puts VAP-1 in the same conceptual category as other stromal and myeloid targets currently being explored to widen the benefit of immunotherapy, from TGF-beta inhibitors to CSF1R blockade. What distinguishes VAP-1, however, is its accessibility. Because it is expressed on the luminal surface of endothelial cells, it is directly exposed to the bloodstream, meaning that both therapeutic antibodies and small molecules can reach it without having to penetrate tumor tissue. That same accessibility underpins a second translational avenue: molecular imaging. The review describes the development of VAP-1-specific ligands labeled with positron-emitting isotopes such as gallium-68, which can be used in PET scans to visualize VAP-1 expression in vivo. In principle, such imaging agents could support theranostic applications, allowing clinicians to stratify patients according to the VAP-1 status of their tumors, to select those most likely to benefit from VAP-1-targeted therapy, and to assess therapeutic response in real time rather than waiting for anatomical changes on conventional scans.

The hepatocellular carcinoma literature adds an epidemiological dimension to the story. VAP-1 has long been studied in the context of liver inflammation, where serum levels rise in conditions such as nonalcoholic fatty liver disease, alcoholic liver disease, chronic hepatitis B and C, and primary sclerosing cholangitis. Because hepatocellular carcinoma typically arises on a background of chronic inflammation and fibrosis, the review examines whether VAP-1 contributes directly to liver tumor biology or simply reflects the inflamed, cirrhotic terrain in which liver cancers develop. The emerging picture suggests both are true to some degree: elevated VAP-1 in the diseased liver promotes the vascular and stromal changes that precede malignancy, and continued expression in established tumors sustains the microenvironmental conditions that support their growth.

None of this means VAP-1 is about to become a household name in cancer medicine overnight. The review is candid about the challenges. Biomarker studies vary in design, sample size and the analytical methods used to measure VAP-1, whether by immunohistochemistry on formalin-fixed paraffin-embedded tissue, quantitative polymerase chain reaction, or ELISA on plasma samples, making cross-study comparisons difficult. Circulating sVAP-1 is also elevated in a range of non-cancerous inflammatory, metabolic and cardiovascular conditions, including type 2 diabetes mellitus, chronic kidney disease and heart failure, which limits its specificity as a diagnostic marker and means it must be interpreted in clinical context. On the therapeutic side, drugs developed for inflammatory indications were optimized for different patient populations, dose ranges and safety endpoints, and their efficacy in cancer remains to be demonstrated in properly powered clinical trials. The authors also note that completely suppressing a molecule involved in normal leukocyte trafficking raises questions about long-term immunological consequences that preclinical models cannot fully answer.

What the review ultimately offers is a roadmap. It consolidates evidence that VAP-1 overexpression is a recurring feature of aggressive tumors, that its dual adhesive and enzymatic functions converge on angiogenesis and immune suppression through hydrogen peroxide-mediated redox signaling, and that its blockade can cooperate with checkpoint immunotherapy in preclinical systems. It also points to imaging agents and soluble biomarkers as tools that could bring VAP-1 biology out of the laboratory and into the clinic, enabling patient selection and response monitoring in ways that few stromal targets currently allow. If ongoing translational efforts bear fruit, the molecule that quietly helps immune cells cross blood vessel walls during inflammation may find a second career as a bullseye on the tumor vasculature, a window into the tumor microenvironment and a lever for prying open cancers that have so far resisted the immune system’s advances.

The research team led by Si, Mo, Zhao, and colleagues capitalized on the concept of microbubble-mediated drug delivery, an area rapidly gaining traction in medical sciences. Microbubbles, tiny gas-filled spheres traditionally used as contrast agents in ultrasound imaging, have emerged as versatile vehicles for targeted therapy. By conjugating these microbubbles with molecules that bind to E-selectin—a key cell adhesion molecule upregulated on inflamed renal endothelium—the researchers achieved highly selective delivery of therapeutic agents to sites of injury within the kidney microvasculature.

Cisplatin, an effective chemotherapeutic drug for various malignancies, unfortunately has nephrotoxicity as a significant dose-limiting side effect. It induces AKI primarily through oxidative stress, inflammation, and apoptosis of renal tubular cells. Current renoprotective strategies mainly involve hydration and dose reduction, which are often insufficient. Methylprednisolone, a potent corticosteroid with anti-inflammatory and immunosuppressive properties, has been recognized for its potential renal benefits. However, systemic administration limits its therapeutic index due to widespread side effects, prompting the need for targeted delivery systems to localize its action.

Utilizing E-selectin as a biomarker for inflamed endothelium provided the research team with a unique targeting mechanism. E-selectin is transiently expressed on activated endothelial cells during inflammation, playing a pivotal role in leukocyte rolling and adhesion, thus marking the loci of renal injury precisely. By loading methylprednisolone onto these engineered microbubbles, the scientists sought to increase drug concentration at the site of injury while minimizing systemic exposure and toxicity.

The utilization of ultrasound is a critical aspect of this therapeutic platform. Ultrasound waves can induce the cavitation of microbubbles, leading to their controlled rupture and localized drug release. This synergistic combination optimizes drug delivery in the microenvironment of the injured kidney, enhancing cellular uptake and therapeutic efficacy. Moreover, ultrasound itself aids in temporarily increasing vascular permeability, facilitating deeper penetration of the drug.

In experimental trials involving rats subjected to cisplatin-induced AKI, this novel therapeutic modality demonstrated remarkable efficacy. Compared to control groups receiving systemic methylprednisolone or untargeted microbubbles, rats treated with E-selectin-targeted microbubbles combined with ultrasound experienced significantly reduced renal inflammation, improved tubular epithelial survival, and lowered serum creatinine levels, a crucial marker of renal function.

Histopathological examinations revealed diminished infiltration of inflammatory cells and preservation of renal tubular morphology in treated animals. These findings were corroborated by molecular analyses showing downregulation of pro-inflammatory cytokines and markers of oxidative stress. Such multifaceted protection is indicative of the synergistic effects of targeted methylprednisolone delivery and ultrasound-mediated enhancement of bioavailability.

One of the most striking aspects of this study is the precise spatiotemporal control afforded by integrating ultrasound with microbubble technology. Unlike conventional drug administration, this approach allows clinicians to noninvasively orchestrate drug release exactly when and where it is needed. This precision reduces off-target effects and may allow for higher effective doses without increasing systemic toxicity, a major limitation encountered in current steroid therapies.

Beyond its immediate implications for AKI, this platform opens avenues for treating myriad renal pathologies characterized by endothelial inflammation and injury, such as glomerulonephritis, diabetic nephropathy, and ischemia-reperfusion injury. The adaptability of the microbubble surface for binding various ligands suggests potential customization for diverse targets and therapeutic agents, highlighting the versatility of this approach.

The study also addresses important safety considerations. The combined treatment did not show adverse effects on cardiovascular parameters or provoke excessive immune responses, reflecting the biocompatibility of the microbubbles and the specificity of targeting. This safety profile is fundamental for translational prospects, as it indicates tolerability in a systemic context.

Technically, the researchers achieved meticulous engineering of the microbubbles, optimizing size, shell composition, and ligand density to balance stability in circulation with efficient ultrasound-triggered release. Additionally, they calibrated ultrasound parameters to maximize therapeutic effects while minimizing tissue damage, underscoring the importance of interdisciplinary collaboration between bioengineers, pharmacologists, and clinicians.

While the study was conducted in animal models, it lays crucial groundwork for clinical trials. The ability to steer drugs to injured renal tissue noninvasively could address longstanding challenges in nephrology therapeutics, including the narrow therapeutic window and lack of targeted drug delivery options. Future investigations will need to establish scalability, dosing regimens, and long-term outcomes in human patients.

Interestingly, this technology might also lend itself to diagnostic applications. Given that E-selectin expression denotes active inflammation, such microbubbles could function as dynamic probes in ultrasound imaging to detect early kidney injury, enabling timely intervention. This theranostic duality exemplifies the cutting-edge nature of this research.

Overall, the convergence of targeted molecular recognition, nano-engineered delivery systems, and ultrasound technology embodied in this study represents a paradigm shift. It underscores how precision medicine principles can be actualized in renal disease management, moving beyond symptom control to sophisticated intervention at the cellular and molecular level. As contemporary medicine grapples with complex organ injuries, such innovative therapies exemplify the transformative potential of bioengineering advances.

In sum, the development of E-selectin-targeted microbubbles combined with ultrasound-induced drug release markedly enhances the renoprotective efficacy of methylprednisolone in cisplatin-induced acute kidney injury. This breakthrough in targeted delivery technology could redefine treatment modalities not only for AKI but also for a broad spectrum of inflammatory kidney diseases, portending a future where precision-directed therapeutics improve patient outcomes dramatically.

Subject of Research: Acute kidney injury; targeted drug delivery; E-selectin; microbubbles; ultrasound; methylprednisolone; cisplatin nephrotoxicity

Article Title: E-selectin-targeted microbubbles combined with ultrasound improves renoprotective effects of methylprednisolone on cisplatin-induced acute kidney injury in rats

Article References:
Si, R., Mo, L., Zhao, C. et al. E-selectin-targeted microbubbles combined with ultrasound improves renoprotective effects of methylprednisolone on cisplatin-induced acute kidney injury in rats. Sci Rep (2026). https://doi.org/10.1038/s41598-026-47547-x

Image Credits: AI Generated