Wilms tumor, also known as nephroblastoma, arises in the developing kidney and accounts for the vast majority of pediatric renal malignancies. More than 90 percent of children are diagnosed with the favorable-histology form, but outcomes vary considerably across patient cohorts. The picture is far grimmer for the 5 to 10 percent of cases classified as high-risk—including metastatic blastemal-type tumors, diffuse anaplastic disease, chemotherapy-refractory tumors, and multiply relapsed cancers—which carry survival rates below 50 percent even after aggressive multimodal therapy. Survivors of intensive radiochemotherapy frequently endure severe long-term side effects that diminish their quality of life. These realities have long motivated researchers to search for molecular vulnerabilities that could enable more individualized and less toxic treatments.

The new study began with a well-known hallmark of cancer: metabolic reprogramming. Tumor cells preferentially break down glucose into lactate even when oxygen is abundant, a phenomenon called the Warburg effect, leading to lactate buildup in the tumor microenvironment. Previous metabolomics work had already flagged elevated lactate as a signature distinguishing Wilms tumor tissue from normal kidney tissue, and a retrospective cohort study showed that higher lactate dehydrogenase activity independently predicts increased recurrence risk in pediatric patients. The research team confirmed these patterns directly, analyzing 52 pairs of Wilms tumor specimens and matched adjacent normal tissues collected at Qilu Hospital of Shandong University. Tumor tissues contained significantly less glucose and significantly more lactate than their normal counterparts, consistent with hyperactive glycolysis.

Lactate, once dismissed as a mere metabolic waste product, is now understood to be a versatile molecule that serves as an energy substrate, a signaling agent, and—critically—an epigenetic regulator. In 2019, researchers first identified histone lactylation as a novel epigenetic modification that directly modulates gene transcription on chromatin. Since then, histone lactylation has been implicated in immune evasion, metabolic reprogramming, and therapeutic resistance across many cancers. The process is enzyme-dependent: the acetyltransferase p300 acts as a writer that deposits lactyl groups onto histones, while HDAC1-3 and sirtuins serve as erasers that remove them. Because these same enzymes also manage histone acetylation, the two modifications share overlapping machinery, raising the possibility that lactylation plays an important but overlooked role in Wilms tumor biology.

Using immunohistochemistry and western blotting on the clinical specimens, the team found that pan-lysine lactylation and H3K18 lactylation were the most prominently elevated modifications in tumor tissue. Survival analysis showed that only high levels of these two marks correlated with significantly poorer event-free survival among the 52 patients studied. To probe function, the researchers manipulated lactylation levels in two Wilms tumor cell lines, WiT49 and WT-CLS1, using sodium lactate to raise intracellular lactate and the glycolysis inhibitors 2-deoxy-D-glucose and oxamate to lower it. The results were striking: boosting lactylation enhanced cell proliferation and migration in a dose-dependent manner, while suppressing lactylation markedly reduced these malignant behaviors.

To identify the genes controlled by H3K18 lactylation, the team integrated public ChIP-seq datasets with RNA-sequencing data from 126 Wilms tumor patients in the TARGET database. Cross-referencing genes bound by the H3K18la mark with genes upregulated in tumors yielded 302 candidates, which were then filtered through Cox regression analyses of patient survival data. Three genes emerged with independent prognostic significance: PSRC1, RFXAP, and GLRX3. Only PSRC1, however, responded specifically to changes in lactylation levels—its mRNA rose with sodium lactate treatment and fell with oxamate. Chromatin immunoprecipitation experiments confirmed that H3K18la was robustly enriched at the PSRC1 promoter in Wilms tumor cells, and that the writer enzyme p300 was required for this deposition. Importantly, the closely related acetylation mark H3K18ac remained unchanged across all treatments, demonstrating that p300 regulates PSRC1 specifically through lactylation rather than acetylation.

PSRC1 itself proved to be a potent oncogenic driver. The protein, also known as DDA3, is a mitotic regulator previously implicated in small cell lung cancer, breast cancer, and hepatocellular carcinoma. In Wilms tumor, high PSRC1 expression predicted poorer overall survival, with area under the curve values of 0.71 to 0.73 for one-, three-, and five-year survival predictions, and multivariate analysis confirmed it as an independent prognostic risk factor. Mechanistically, the team discovered that PSRC1 acts as a molecular competitor: it binds directly to the kinase domain of AKT through its proline-rich P-X-X-P domain spanning amino acids 103 to 246, thereby blocking the tumor suppressor PTEN from binding AKT and dephosphorylating it. Co-immunoprecipitation, mass spectrometry, immunofluorescence, and molecular docking—all supporting a stable interaction with a binding free energy of minus 28.4 kilocalories per mole—confirmed the competitive binding model. The consequence is sustained activation of the AKT/mTOR pathway, which stabilizes the HIF-1α protein, a master transcription factor that promotes glycolysis and tumor growth.

The final piece of the puzzle closed the loop. HIF-1α, stabilized by PSRC1-driven AKT signaling, was found to bind directly to a hypoxia response element within the PSRC1 promoter, further amplifying PSRC1 transcription. Dual-luciferase reporter assays demonstrated that hypoxia increased promoter activity only when the response element was intact, and HIF-1α knockdown blunted this activation. The result is a positive feedback circuit: H3K18 lactylation activates PSRC1, PSRC1 activates AKT/mTOR/HIF-1α signaling, and HIF-1α returns to boost PSRC1 expression, creating an escalating cycle of oncogenic signaling. Animal experiments corroborated the entire axis in vivo. In nude mouse xenograft models, PSRC1 knockdown slowed tumor growth and reduced lung metastatic burden, while PSRC1 overexpression accelerated growth, promoted lung colonization, and partially reversed the tumor-suppressive effects of oxamate, which was administered daily at 500 milligrams per kilogram.

The therapeutic implications are considerable, though tempered by practical challenges. The authors highlight three promising intervention points: inhibiting lactate production with agents such as oxamate, which has shown antitumor activity and low toxicity in preclinical models but suffers from poor membrane permeability that nanoparticle delivery could overcome; targeting the writer enzyme p300 with inhibitors such as CCS1477, which has advanced to phase I/II clinical trials in other cancers; and disrupting the feedback loop itself through AKT/mTOR inhibitors, peptide inhibitors designed to block the PSRC1-AKT interaction interface, or HIF-1α inhibitors. Each strategy faces hurdles, including systemic toxicity, the heightened safety requirements of pediatric oncology, and the risk that single-target inhibition will be undermined by the very feedback loop the study describes. The authors also note limitations: the clinical cohort was relatively small, genetically engineered animal models were not used, and the identity of the eraser enzymes that remove H3K18 lactylation in Wilms tumor remains unknown.

Nevertheless, the study represents the first demonstration of a histone lactylation-driven feedback circuit in Wilms tumor and bridges three previously separate domains—metabolic reprogramming, epigenetic modification, and oncogenic signaling. By showing that a metabolic byproduct can be converted into a durable transcriptional program that fuels cancer progression, the work adds Wilms tumor to the growing list of malignancies shaped by lactylation and provides a molecular rationale for combining metabolic inhibitors with signaling blockade. For the children with high-risk disease who currently face the bleakest odds, such rational combination strategies may ultimately offer a path toward more effective and less toxic therapy.

Subject of Research: Histone H3K18 lactylation and the PSRC1/AKT/HIF-1α feedback loop in Wilms tumor progression

Article Title: Histone H3K18 Lactylation Promotes the Malignant Progression of Wilms Tumor via a PSRC1/AKT/HIF‐1α Positive Feedback Loop

Article References: Wang, Y., Gao, H., Zhang, B., Li, X., Li, D., Cao, A., & Sun, F. (2026). Histone H3K18 Lactylation Promotes the Malignant Progression of Wilms Tumor via a PSRC1/AKT/HIF‐1α Positive Feedback Loop. Advanced Science, 13(56), Article e76579. https://doi.org/10.1002/advs.76579

Image Credits: AI Generated

DOI: 10.1002/advs.76579

Keywords: Wilms tumor, histone lactylation, H3K18la, PSRC1, AKT signaling, HIF-1α, p300, PTEN, Warburg effect, epigenetics, pediatric cancer, metabolic reprogramming

Wilms tumor, also known as nephroblastoma, is the most common malignant renal tumor of childhood, typically arising in children under the age of five. It develops from embryonal kidney tissue that fails to mature properly, and in a small but significant proportion of patients it appears in both kidneys simultaneously. Bilateral disease presents a particular therapeutic dilemma: surgeons must balance the need to remove cancerous tissue against the imperative to preserve enough functioning kidney for a lifetime of renal health. It is precisely this tension that has shaped the modern treatment paradigm, in which chemotherapy is given first to shrink the tumors, allowing later surgery to be as kidney-sparing as possible.

The central tenet of that paradigm is that diagnosis in typical cases can be made on clinical and radiological grounds alone. The Children’s Oncology Group in North America and the SIOP Renal Tumour Study Group in Europe and beyond are the two cooperative bodies whose protocols govern nearly all contemporary Wilms tumor treatment. Both groups discourage routine diagnostic biopsy in children whose imaging findings are characteristic, permitting it only in narrowly defined exceptions such as tumors that behave atypically on scans or cases where the diagnosis is genuinely uncertain. Crucially, neither group recommends biopsy of bilateral disease at initial presentation, because the imaging appearance of bilateral masses in a young child is considered sufficiently specific to justify starting neoadjuvant chemotherapy without histological confirmation.

The rationale behind this approach is not merely administrative. Upfront nephrectomy or biopsy can rupture or seed tumor cells, upstage disease, and complicate later surgical planning. More fundamentally, any invasive procedure performed before chemotherapy begins introduces a window of potential morbidity during which the child receives no anti-cancer therapy. In the case described by Aujla, that window proved disastrous. The biopsy of the right kidney, sampled at an outside facility prior to referral, returned a non-diagnostic result, providing no useful information while breaching the renal architecture. The left-sided sample did confirm Wilms tumor, but at a cost that would soon become apparent.

Within a short time, the child developed a draining sinus at the right biopsy site, discharging pus persistently. Clinical evaluation and subsequent surgical exploration revealed the underlying cause: a pelviureteric fistula, an abnormal communication between the renal collecting system and the ureter that allowed urine to leak into the tissues, creating a nidus for infection. Cultures identified Escherichia coli, and the infection proved refractory to standard management. For an 18-month-old already facing bilateral kidney tumors, the complication transformed a straightforward treatment pathway into a prolonged ordeal, with both the start of neoadjuvant chemotherapy and the timing of definitive surgery pushed back significantly.

The case is a textbook illustration of why the cooperative groups have drawn such firm lines around biopsy. A needle traversing the kidney does not simply sample tissue; it can lacerate the collecting system, provoke bleeding, and open a channel between a normally sterile urinary tract and the skin. In centers with immediate pediatric surgical, urological, and infectious disease support, such complications are rare and manageable. In resource-constrained settings, where imaging guidance may be limited and referral pathways circuitous, the same procedure can produce complications that are difficult to diagnose and harder to fix. The report emphasizes that this biopsy was performed outside a specialized pediatric oncology center, a detail that recurs in discussions of avoidable harm in childhood cancer care across low- and middle-income countries.

Yet the guidelines are not absolute, and the report takes care to situate the case within a nuanced evidence landscape. Emerging data have supported the safety of image-guided biopsy in specific unilateral cases, particularly where imaging is atypical and the differential diagnosis includes entities such as renal cell carcinoma that would change the surgical plan entirely. Aujla’s analysis, however, warns against extrapolating those findings to bilateral tumors. The hemodynamics, anatomy, and therapeutic strategy of bilateral disease are different: the goal is maximal nephron preservation after chemotherapy response has been assessed, and the protocols have built in a mechanism for exactly that. Under the Children’s Oncology Group’s AREN0534 protocol, for example, selective biopsy is permitted later in the treatment course, guided by the patient’s response to initial chemotherapy and performed before definitive surgery, when it can genuinely inform the extent of resection rather than merely confirm what imaging already suggested.

The historical arc of Wilms tumor management explains how this consensus emerged. Early surgical series treated the tumor as a straightforward resection problem, and upfront nephrectomy was standard. The National Wilms Tumor Study Group in the United States and its European counterpart, which later evolved into the SIOP framework, demonstrated in successive randomized trials that preoperative chemotherapy in Europe, and carefully sequenced surgery and chemotherapy in North America, produced survival rates that now exceed ninety percent for localized disease. Along the way, the trials also catalogued the harms of unnecessary intervention, including tumor rupture at surgery and the staging consequences of preoperative procedures. Biopsy, once considered a reasonable diagnostic step, was progressively restricted as imaging quality improved and the characteristic appearance of nephroblastoma became reliably recognizable on ultrasound and computed tomography.

For pediatricians, who are typically the first clinicians to encounter a child with an abdominal mass, the practical lesson is one of restraint and rapid referral. The report notes that premature referral for biopsy or upfront nephrectomy remains a recurring error, often driven by the instinct that tissue diagnosis must precede cancer treatment. In Wilms tumor, that instinct is inverted: in a young child with bilateral renal masses and typical imaging, the protocol-compliant move is to refer immediately to a pediatric oncology center and begin chemotherapy, reserving tissue sampling for the defined scenarios in which it changes management. Every week spent pursuing a non-diagnostic biopsy is a week of untreated disease and, as this case shows, a week in which iatrogenic injury can compound the burden of malignancy.

The broader significance of the report lies in its setting. Low- and middle-income countries face a disproportionate share of global childhood cancer deaths, and the reasons are structural: late presentation, fragmented referral systems, limited access to specialized pathology and imaging, and well-intentioned interventions at facilities without pediatric oncology capability. Case reports like this one function as evidence for systems-level change, arguing for clear referral pathways, education of frontline providers about protocol-based management, and restraint in procedures that guidelines explicitly discourage. The child at the center of this report ultimately faced both her tumor and its man-made complications, her treatment delayed by an infection that should never have had a route into her urinary tract. Her story, documented with the consent of her guardians and published openly, adds a human dimension to a statistical consensus, reminding clinicians everywhere that in pediatric oncology, following the protocol is not bureaucratic caution but a safeguard measured in kidneys, in infections avoided, and in time that no child with cancer can afford to lose.

Subject of Research: Complications of guideline-discordant renal biopsy in a child with suspected bilateral Wilms tumor

Article Title: Guideline-discordant biopsy in suspected bilateral Wilms tumor and its surgical complications: a case report from a low-resource setting and review of current protocols

Article References: Aujla, R. (2026). Guideline-discordant biopsy in suspected bilateral Wilms tumor and its surgical complications: a case report from a low-resource setting and review of current protocols. BMC Pediatrics. https://doi.org/10.1186/s12887-026-07680-y

Image Credits: AI Generated

DOI: 10.1186/s12887-026-07680-y

Keywords: Wilms tumor, bilateral renal disease, pediatric oncology, renal biopsy, SIOP-RTSG, Children's Oncology Group, AREN0534, neoadjuvant chemotherapy, pelviureteric fistula, needle biopsy complications, low-resource settings, BMC Pediatrics