bims-raghud 2026-09-06 papers

Issue of 2026–09–06
four papers selected by
Irene Sambri, TIGEM

Virchows Arch. 2026 Sep 03.

Aggressive high-grade papillary-patterned renal cell carcinomas harboring FLCN mutations: expanding the clinicopathological spectrum in Birt-Hogg-Dubé syndrome and sporadic cases.

Xiao-Tong Wang, Ru Fang, Sheng-Bing Ye, Xuan Wang, Rui Li, Yan He, Ru-Song Zhang, Qiu-Yuan Xia, Ming Zhao, Qiu Rao.

Folliculin (FLCN)-mutated renal tumors, in the setting of Birt-Hogg-Dubé (BHD) syndrome or sporadically, typically show low-grade eosinophilic morphology and follow an indolent clinical course; however, rare high-grade variants with more aggressive behavior remain poorly defined and underrecognized. To better characterize this unusual subset, we identified six high-grade renal cell carcinomas (RCCs) and performed integrated clinicopathologic, immunohistochemical, molecular, and clinical follow-up analyses. All tumors demonstrated infiltrative growth, extensive necrosis, variable desmoplastic stroma, and high-grade nuclear features. They exhibited papillary/tubulopapillary and solid growth patterns, mixed eosinophilic and clear cell cytology, focal biphasic morphology, and prominent nucleoli, overlapping morphologically with high-grade papillary RCC, FH-deficient RCC, and TFE3- or TFEB-rearranged RCC. Targeted DNA sequencing identified FLCN frameshift mutations in all cases, including four germline mutations, one likely germline mutation, and one somatic mutation, without additional alterations characteristic of other established RCC subtypes. In keeping with the FLCN-mutated phenotype, all tumors extensively and strongly expressed GPNMB. Clinically, three patients had features consistent with BHD syndrome; one additional patient lacked typical pulmonary and cutaneous findings but was confirmed to carry a germline mutation; another could not be definitively classified as having BHD and was considered suspected; and the remaining one had no clinical evidence of BHD and was considered likely sporadic. At last follow-up, three patients were free of recurrence or metastasis at 10, 25, and 7 months; the remaining three developed distant metastases, including two who died of disease at 17 and 26 months postoperatively and one who remained alive with metastatic disease at 85 months. Our findings expand the morphologic spectrum of FLCN-mutated renal tumors and the genetic landscape of papillary-patterned RCCs, raising awareness of this aggressive subset and supporting consideration of FLCN testing in morphologically overlapping high-grade papillary tumors.

Keywords: Birt-Hogg-Dubé; Folliculin; High-grade; Papillary-patterned; Renal cell carcinoma

DOI: https://doi.org/10.1007/s00428-026-04693-x

Clin J Am Soc Nephrol. 2026 Sep 03.

Predictive Value of Urine Tubular Biomarkers on Kidney Outcomes: Observations from EMPA-KIDNEY.

EMPA-KIDNEY Collaborative Group

BACKGROUND: Urine tubular biomarkers have previously been associated with chronic kidney disease (CKD) progression independently of estimated glomerular filtration rate (eGFR) and albuminuria. We evaluated whether nine urine tubular biomarkers could improve prediction of kidney failure beyond serum creatinine and urine albumin-to-creatinine ratio among adults with CKD.
METHODS: Among 5100 participants in EMPA-KIDNEY, a randomized trial which assessed the effects of empagliflozin 10 mg versus matching placebo among patients with CKD at risk of progression, nine urine creatinine-indexed tubular biomarkers were measured including alpha-1 microglobulin, dickkopf-3, epidermal growth factor [EGF], interleukin-18, kidney injury molecule-1 [KIM-1], monocyte chemoattractant protein-1 [MCP-1], neutrophil gelatinase-associated lipocalin, uromodulin, and human cartilage glycoprotein-40. Outcomes were kidney disease progression ('treated kidney failure', renal death, or sustained ≥40% eGFR decline) and treated kidney failure (maintenance dialysis or kidney transplant). Relative to models based on the linear predictor of the kidney failure risk equation (KFRE), improvements in discrimination were estimated with further addition of the nine tubular biomarkers using absolute difference in Uno's C-index.
RESULTS: Over median 3.5 years of follow-up, 1191 participants experienced kidney disease progression and 461 experienced treated kidney failure. KFRE demonstrated excellent discrimination for treated kidney failure [C-index 0.858 (0.840,0.874)] and moderate discrimination for kidney disease progression [0.724 (0.705,0.743)]. Addition of three biomarkers (MCP-1, KIM-1, and EGF) most strongly associated with CKD outcomes yielded some further improvement in predicting kidney failure [absolute difference 0.014 (0.009,0.024)] and kidney disease progression [0.038 (0.026,0.053)]. Prediction of kidney outcomes were only slightly improved when further expanding from three to all ning tubular biomarkers.
CONCLUSION: In a wide range of causes of CKD, adding three urine tubular biomarkers (MCP-1, KIM-1, EGF) to KFRE improves estimates of risk of CKD progression.

DOI: https://doi.org/10.2215/CJN.0000001203

Sci Adv. 2026 Sep 04. 12(36): eaef8132

Mitochondrial superoxide-induced mitohormesis is mediated by citrate and cardioprotective.

Mitohormesis, whereby transient mitochondrial stress induces adaptive signaling, promotes organismal resilience and longevity in invertebrates, but how this operates in mammals and the underlying metabolic signals involved remain unclear. Using a mouse model of mitohormesis, we show that transient mitochondrial superoxide stress during embryogenesis reprograms the adult heart to enhance mitochondrial biogenesis and antioxidant capacity. These adaptations confer protection against mitochondrial and oxidative injury in models of doxorubicin-induced cardiotoxicity, preserving mitochondrial content and preventing cardiac dysfunction and remodeling. Using a cell model of superoxide-mediated mitohormesis, we find that inhibition of mitochondrial aconitase promotes citrate export to the cytosol, where its conversion to acetyl-coenzyme A drives histone acetylation and mitohormetic protection from oxidative stress. Preventing mitochondrial citrate export abolishes these adaptations, while Aco2 silencing or citrate supplementation recapitulates the response. Together, our findings identify mitochondrial citrate as a redox-sensitive second messenger linking mitochondrial superoxide stress to durable epigenetic and mitohormetic remodeling.

DOI: https://doi.org/10.1126/sciadv.aef8132

Cell Death Differ. 2026 Sep 02.

Renal cell carcinoma: molecular understanding and therapeutic development.

Tao Hou, Xiangmei Hua, Wei Ni, Peiqiang Yan, Hiroyuki Inuzuka, Wenyi Wei.

Renal cell carcinoma (RCC) is a highly heterogeneous malignancy characterized by diverse molecular alterations and dynamic evolutionary trajectories. Advances in genomics and molecular profiling have shifted RCC management from morphology-based classification toward molecularly informed diagnosis and therapy. In this review, we integrate recent multi-omics and clinical advances to define the evolving biological and therapeutic landscape of RCC. We highlight how the 2022 WHO classification incorporates molecular features to refine pathological subtyping and summarize key driver genetic alterations underlying major RCC entities. We then discuss insights derived from multi-region sequencing studies, including TRACERx Renal, which demonstrate how intratumoral heterogeneity, branched evolution, and clonal selection shape disease progression and therapeutic resistance. We further examine subtype-specific metabolic programs, with particular emphasis on dysregulation of the AMPK-mTORC1 signaling axis and distinct metabolic dependencies across clear cell and non-clear-cell RCC. We additionally highlight cell death regulation and differentiation plasticity as integrative themes that connect molecular pathogenesis to therapeutic vulnerability, with sarcomatoid and rhabdoid dedifferentiation as a key example. Finally, we review the evolution of systemic therapies, from VEGF-targeted tyrosine kinase inhibitors to immune checkpoint-based combinations, and outline emerging strategies, including HIF-2α inhibition, PD-1/VEGF bispecific antibodies, and subtype-specific metabolic and epigenetic dependencies. Collectively, this review provides an integrated framework linking molecular evolution, metabolic reprogramming, and therapeutic development, with the goal of advancing biomarker-driven precision management in RCC.

DOI: https://doi.org/10.1038/s41418-026-01857-9