bims-raghud 2026-04-26 papers

Issue of 2026–04–26
five papers selected by
Irene Sambri, TIGEM

Cell Death Dis. 2026 Apr 21. pii: 397. [Epub ahead of print]17(1):

TGF-β/SMAD4/14-3-3σ/TFEB axis promotes mesenchymal-epithelial transition and inhibits autophagy in colorectal cancer.

Xiaoyan Chen, Markus Winter, Matjaz Rokavec, Janine König, Heiko Hermeking.

14-3-3σ is a p53-inducible gene with tumor suppressive properties and SMAD4 is a transcription factor encoded by a tumor suppressor gene, which is commonly inactivated in colorectal cancer (CRC). Here, 14-3-3σ was characterized as direct transcriptional target of SMAD4. TGF-β treatment of tumoroids derived from CRC patients and mouse models resulted in a SMAD4-dependent induction of 14-3-3σ. In murine, intestinal epithelia, the apical expression of 14-3-3σ was dependent on Smad4. Ectopic SMAD4 or 14-3-3σ promoted mesenchymal-to-epithelial transition (MET) and suppressed invasion, migration, and autophagy of CRC cells. As experimental inactivation of 14-3-3σ abolished these tumor-suppressive functions of SMAD4, 14-3-3σ mediates these effects of SMAD4. Inhibition of autophagy and promotion of MET by SMAD4 was mediated by inhibition of TFEB via binding and sequestration of TFEB by 14-3-3σ. The association of 14-3-3σ and TFEB was dependent on phosphorylation of the TFEB serine 211 residue, which is a target of mTORC1. Taken together, the TGF-β/SMAD4/14-3-3σ/TFEB axes characterized here antagonizes epithelial plasticity and autophagy. Thereby, it may ultimately suppress the progression of CRC and other types of cancer.

DOI: https://doi.org/10.1038/s41419-026-08733-x

Immunol Invest. 2026 Apr 24. 1-15

TFEB Activator Curcumin Analog C1 Downregulates PKM2 and Alleviates Inflammatory Injury in Endotoxemic Mice.

Yanliuying Zhu, Xinyan Zan, Kerui Fan, Jiao Wang, Ying Zhi, Jinlin Liu, Yongqiang Yang, Li Zhang.

OBJECTIVE: Autophagy dysfunction results in the accumulation of pro-inflammatory components and drives inflammatory injury. Transcription factor EB (TFEB) is a master regulator of autophagy and a novel target for controlling inflammatory injury. Curcumin analog C1 directly binds to and activates TFEB, but its anti-inflammatory effects remain unclear.
METHODS: The anti-inflammatory and protective effects of curcumin analog C1 were investigated in lipopolysaccharide (LPS)-induced endotoxemia mice.
RESULTS: Curcumin analog C1 reversed LPS-induced autophagy dysfunction, downregulated pyruvate kinase M2 (PKM2), and reduced pro-inflammatory cytokines including TNF-α, IL-6, and MCP-1. It also attenuated systemic abnormalities, alleviated lung injury, and decreased blood urea nitrogen (BUN), brain-type natriuretic peptide (BNP), and extracellular DNA levels.
CONCLUSIONS: Curcumin analog C1 exhibits potential pharmacological value in the control of inflammatory injury.Thank you for your assistance.

Keywords: Inflammation; TFEB; autophagy; pyruvate kinase M2

DOI: https://doi.org/10.1080/08820139.2026.2663149

Nephrol Dial Transplant. 2026 Apr 21. pii: gfag091. [Epub ahead of print]

Modeling Podocytopathies with Kidney Organoids.

Marina de Cos, Mona Zeghal, Kristin Meliambro.

Kidney organoids have emerged as powerful in vitro models for investigating normal kidney physiology, disease development, and drug screening, offering unique advantages over traditional cell culture and animal-based systems. By recapitulating glomerular podocyte-like structures, these models have provided unique opportunities to study the pathophysiology of podocytopathies. While prior reviews have summarized novel applications of kidney organoids to kidney disease research in general, these have largely focused on renal tubular physiology and injury mechanisms, for which a greater body of data currently exists. In this review, however, we solely consider kidney organoid-based studies to date that have modeled diverse forms of podocyte injury. We first discuss investigations of drug-induced podocyte injury via kidney organoids, with consideration of their potential future role as high-throughput platforms for preclinical drug screening. We then examine how organoids have furthered research into the genetics of kidney disease, particularly monogenic forms of focal segmental glomerulosclerosis (FSGS) and collagenopathies, and their potential use to assess variants of uncertain significance and mutation-specific therapeutic responses. We additionally highlight how organoid systems have been employed to model complex glomerular disorders, including APOL1-mediated kidney disease, virus-induced podocyte injury, diabetic nephropathy, and podocyte senescence. We further consider the application of kidney organoids to the study of autoantibody-mediated podocytopathies, an area of emerging research. Finally, we provide an overall critique of the strengths and limitations of kidney organoids models specifically in the context of podocytopathy research, emphasizing unmet research needs and opportunities to enhance their fidelity, maturity, and functional integration as precision medicine tools.

Keywords: FSGS; glomerular disease modeling; kidney organoids; podocytopathies; precision medicine

DOI: https://doi.org/10.1093/ndt/gfag091

Hum Pathol. 2026 Apr 16. pii: S0046-8177(26)00091-2. [Epub ahead of print]173 106122

Renal tumors harboring FLCN mutations: Case series from clinical practice.

Chien-Kuang C Ding, Emily Chan, Tamara L Lotan, Jen-Fan Hang, Nancy Y Greenland, Bradley A Stohr, Jeffry P Simko, Deepika Sirohi.

BACKGROUND: Renal cell neoplasms with FLCN mutations, classically seen in Birt-Hogg-Dubé (BHD) syndrome typically include oncocytoma, chromophobe RCC, and hybrid oncocytic/chromophobe tumors (HOCT). Recent studies have highlighted FLCN-mutated renal cell carcinomas (RCCs) with unclassified morphologies, raising diagnostic challenges.
METHODS: We retrospectively identified renal tumors with FLCN mutations by targeted next-generation sequencing at our institution (2015-2024). Clinical records, tumor morphology, immunohistochemistry, and genomic profiles were reviewed.
RESULTS: Seven patients were identified. Four exhibited unclassified morphologies with features overlapping with translocation RCC, as well as papillary RCC and eosinophilic solid and cystic (ESC) RCC. One clear cell RCC harbored a secondary probable germline FLCN mutation and TFEB locus amplification, while two were consistent with conventional oncocytic morphology. Germline FLCN mutation was confirmed in two patients with BHD syndrome. Recurrent copy number changes in these tumors included loss of 1p, 15q, 17p and 14q, and gain of 17q. CD117 and CK7 were negative to focal in majority of the cases, TFE3 showed diffuse to focal positivity, while GPNMB was diffusely positive in all 5 cases with material available. Clinical outcomes ranged from indolent disease to metastasis and late recurrence.
CONCLUSIONS: FLCN-mutated RCCs comprise a morphologically heterogeneous yet molecularly defined group. Conventional oncoytic morphology was associated with germline alterations while unclassified morphologies could be associated with somatic alterations and possibly germline mutations. FLCN mutations may also be incidental germline mutations in other RCC subtypes. Tumors with unclassified morphologies evoked morphological and immunohistochemical diagnostic consideration of other oncocytic and papillary RCCs and could be associated with adverse outcomes. Recognition may be aided by diffuse GPNMB expression, but definitive classification, especially in cases without conventional morphology, requires molecular testing. These findings broaden the spectrum of FLCN-driven tumors and support their distinction as a unique molecular entity.

Keywords: Birt-Hogg-Dubé (BHD) syndrome; FLCN-Mutated renal tumors; Glycoprotein non-metastatic B (GPNMB)

DOI: https://doi.org/10.1016/j.humpath.2026.106122

Mol Metab. 2026 Apr 20. pii: S2212-8778(26)00052-9. [Epub ahead of print] 102368

A novel mouse model for cardiovascular-kidney-metabolic syndrome: Bridging metabolic, renal and cardiac dysfunction.

BACKGROUND: CKM syndrome involves obesity, type 2 diabetes (T2D), chronic kidney disease (CKD) and cardiovascular disease (CVD). However, most preclinical models fail to reproduce the progressive renal and cardiac dysfunction characteristic of advanced CKM syndrome, limiting their ability to accurately reflect human disease.
METHODS: Male uninephrectomized (UNx) KK-Ay mice received a high-fat diet (HFD) with or without the vasoconstrictor L-NNA for 13-16 weeks.
RESULTS: UNx + HFD + L-NNA resulted in obesity, hyperglycemia and progressive kidney failure, indicated by a rapid increase in albuminuria and transient hyperfiltration followed by progressive glomerular filtration rate (GFR) decline over three months. Histopathological analysis revealed severe glomerular damage, fibrosis, inflammation and basement membrane thickening, most pronounced in UNx + HFD + L-NNA mice. Renal transcriptomics analysis revealed robust activation of inflammatory and fibrotic pathways, again most pronounced in UNx + HFD + L-NNA mice. In the heart, UNx + HFD + L-NNA resulted in increased ejection fraction and fractional shortening, reduced end-systolic volume and increased left ventricular posterior wall thickness. Alongside pronounced right ventricular fibrosis, this phenotype points toward a phenotype of heart failure with preserved ejection fraction (HFpEF).
CONCLUSIONS: The UNx + HFD + L-NNA KK-Ay model reproduces key metabolic, renal and cardiac components of CKM syndrome. While obesity and hyperglycemia contribute substantially to disease burden, L-NNA-induced hypertension further exacerbates both renal decline and cardiac remodeling. Therefore, this model enables mechanistic investigation and evaluation of therapeutic strategies for CKM syndrome.

Keywords: Cardiovascular-kidney-metabolic syndrome; GFR decline; Glomerulosclerosis; HFpEF; Progressive diabetic kidney disease

DOI: https://doi.org/10.1016/j.molmet.2026.102368