bims-raghud 2026-08-30 papers

bims-raghud

Biomed News

on RagGTPases in human diseases

Issue of 2026–08–30
seven papers selected by
Irene Sambri, TIGEM

MITF Activation Is a Feature of Clear Cell and Conventional Fibrous Papule.
Compartment-Specific iPSC-Derived Cardiomyocytes and Organoids: Differentiation Strategies and Applications in Cardiovascular Disease Modeling.
Enhancing lysosome function via TFEB activation reduces lipofuscin-like granules in the retinal pigment epithelium.
Prenatal mTOR-Inhibitor Therapy for Fetal Cardiac Rhabdomyomas: Indications, Treatment Duration and Perinatal Outcomes.
The dual role of AMPK in cancer metabolic reprogramming.
Challenges of Biomarker Application in Patients with Cardiorenal Syndrome.
Regulatory Roles of Kaempferol on the PI3K/AKT/mTOR Signaling Pathway and Associated MicroRNAs in Different Cancer Types.

J Cutan Pathol. 2026 Aug 28.

MITF Activation Is a Feature of Clear Cell and Conventional Fibrous Papule.

David J Papke, Daniel Pissaloux, Igor Odintsov, Esther Baranov, Jason L Hornick, Arnaud de la Fouchardiere, John Hanna.

  Fibrous papule, also known as angiofibroma, is a common benign cutaneous lesion with a predilection for the nose and, to a lesser extent, other parts of the face. Most cases occur sporadically, although similar lesions occur in tuberous sclerosis where they are sometimes referred to as adenoma sebaceum. In addition to conventional fibrous papule, several morphologic subtypes have been described which are much less common and may be more challenging to recognize. Clear cell fibrous papule is distinguished by its voluminous clear cytoplasm and the expression of NKI-C3, a marker of lysosomes. Here we show that clear cell fibrous papule is characterized by MITF overexpression and activation, and is accompanied by overexpression of GPNMB, a direct transcriptional target of MITF. Surprisingly, MITF overexpression was also seen in both conventional fibrous papule and tuberous-sclerosis-associated fibrous papules, suggesting a potentially unifying cellular feature in all three subtypes of fibrous papule. Furthermore, since the mTOR pathway, which is dysregulated in tuberous sclerosis, regulates the MITF/TFE family of transcription factors, these findings also suggest a potential mechanistic link between sporadic and syndromic fibrous papules.

Keywords:  MITF; angiofibroma; clear cell; fibrous papule; lysosome; melanosome

DOI:  https://doi.org/10.1111/cup.70203
Cells. 2026 Aug 14. pii: 1460. [Epub ahead of print]15(16):

Compartment-Specific iPSC-Derived Cardiomyocytes and Organoids: Differentiation Strategies and Applications in Cardiovascular Disease Modeling.

Aaron D Argall, Rabina Shrestha, Jiyoon Lee, Ming-Tao Zhao.

  Compartment-specific induced pluripotent stem cell (iPSC)-derived cardiomyocytes provide a powerful resource to study cellular and molecular underpinnings of congenital heart disease (CHD) and acquired cardiovascular disease (CVD). Human heart development requires coordinated and complex regulation of key signaling pathways including Notch, BMP, Wnt, Nodal, and Shh during each step of heart morphogenesis. Compartment-specific cardiac cells for modeling the various structures in the heart can be generated by fine tuning these signaling pathways in a sequential manner thereby mimicking spatiotemporal regulation during embryonic heart morphogenesis. In this review, we provide a brief overview of key signaling pathways that are responsible for forming the distinct structures of the heart originating from the first heart field (FHF) and second heart field (SHF). We then summarize recent differentiation protocols that leverage key heart-development related signaling molecules to generate compartment-specific cardiomyocytes and organoids for disease modeling and therapeutic development in cardiovascular disease.

Keywords:  atria; atrioventricular canal; cardiac development; cardiomyocyte; congenital heart disease; induced pluripotent stem cell; outflow tract; ventricle

DOI:  https://doi.org/10.3390/cells15161460
Exp Eye Res. 2026 Aug 24. pii: S0014-4835(26)00371-4. [Epub ahead of print] 111215

Enhancing lysosome function via TFEB activation reduces lipofuscin-like granules in the retinal pigment epithelium.

Ana S Falcão, Mafalda Lopes-da-Silva, Pedro Antas, Cristina Escrevente, Margarida Pedro, Beatriz Felgueiras, Beatriz Caires, Rita Coelho, Inês S Ferreira, Inês P Santos, Thomas Ciossek, Paul Nicklin, Sandra Tenreiro, Miguel C Seabra.

  Age-related macular degeneration (AMD) is the most common blinding disease in the western world and is currently incurable. Although the exact causes of AMD are not clear, the primary origin of pathology appears to be the aged retinal pigment epithelium (RPE) exhibiting signs of lysosomal dysfunction and oxidative damage. RPE is responsible for the daily digestion of photoreceptor outer segments (POS), imposing a heavy continuous burden on the lysosomal network. A cellular model of RPE lysosomal dysfunction can be achieved by feeding RPE with a single pulse of POS, leading to the accumulation of autofluorescence granules (AFG), similar to lipofuscin in vivo. Here we show that synchronous phagocytosis of POS leads to early transient mTOR activation followed by inhibition in late phagosome maturation. One of its substrates, the transcription factor EB (TFEB) increases during phagosome maturation albeit mostly in its inactive phosphorylated form. We questioned whether modulation of the mTOR/TFEB axis could improve POS clearance and hence reduce AFG load. Treatment of POS-fed cells after the appearance of AFGs with rapamycin, an mTORC1 inhibitor results in ∼30% reduction of AFG load. This effect is dependent on active lysosomal enzymes and induction of active dephosphorylated TFEB with consequent activation of GADD34 and lysosomal biogenesis. As a proof of concept, we show that overexpressing a constitutively active form of unphosphorylated TFEB dramatically reduces POS-dependent AFG accumulation. Overall, this study suggests that viral or pharmacological approaches activating the TFEB pathway in the RPE could be beneficial as cell-protective treatment of early/intermediate cases of AMD, acting to delay progression of the disease.

Keywords:  TFEB; autofluorescent granules; lysosomal dysfunction; mTOR; photoreceptor outer segments phagocytosis

DOI:  https://doi.org/10.1016/j.exer.2026.111215
J Clin Med. 2026 Aug 20. pii: 6453. [Epub ahead of print]15(16):

Prenatal mTOR-Inhibitor Therapy for Fetal Cardiac Rhabdomyomas: Indications, Treatment Duration and Perinatal Outcomes.

Ioannis Kyvernitakis, Katharina Schramm, Gert Wiegand, Bernd Feyerabend, Ahmet Alexander Baschat.

  Background: Fetal cardiac rhabdomyomas are strongly associated with tuberous sclerosis complex (TSC). Although many remain asymptomatic and regress spontaneously, large tumors may cause ventricular inflow or outflow obstruction, arrhythmia, impaired ventricular function, pericardial effusion, hydrops fetalis and fetal demise. Transplacental mammalian target of rapamycin (mTOR) inhibition has emerged as a potential rescue therapy. Methods: We performed a narrative review of published reports on prenatal sirolimus or everolimus therapy for fetal cardiac rhabdomyomas in suspected or confirmed TSC. Data was extracted on treatment indication, gestational age at initiation, treatment duration, fetal echocardiographic response, maternal adverse effects, delivery and postnatal outcome. Results: Available evidence consists predominantly of case reports, small case series and retrospective cohorts; no prospective controlled trials were identified. Treatment was generally initiated for progressive or hemodynamically significant disease, particularly ventricular inflow or outflow obstruction, worsening valve regurgitation, arrhythmia, pericardial effusion, ventricular dysfunction or hydrops. Therapy was usually started in the late second or third trimester and continued until hemodynamic stabilization, delivery or planned transition to neonatal treatment. Most reports described tumor regression within 1-3 weeks, accompanied by improved cardiac function and high perinatal survival. However, rebound growth after treatment withdrawal, persistent arrhythmic risk and limited long-term safety data remain important concerns. Conclusions: Prenatal mTOR-inhibitor therapy should be considered an individualized rescue or stabilization strategy for fetuses with life-threatening or progressive cardiac compromise, rather than routine treatment for all fetal rhabdomyomas. Management should be multidisciplinary and guided by fetal hemodynamics, treatment response, maternal tolerance and gestational age.

Keywords:  everolimus; fetal cardiac rhabdomyoma; fetal therapy; hydrops fetalis; mTOR inhibitor; outflow tract obstruction; sirolimus; tuberous sclerosis complex

DOI:  https://doi.org/10.3390/jcm15166453
Mol Biol Rep. 2026 Aug 25. pii: 1456. [Epub ahead of print]53(1):

The dual role of AMPK in cancer metabolic reprogramming.

Xueqing Han, Weiming Zhao.

  Metabolic dysregulation is a core hallmark of tumor cells, which reshapes energy metabolism patterns to meet the demands of rapid proliferation, invasion, metastasis, and drug resistance. AMP‑activated protein kinase (AMPK), as a central regulator of cellular energy homeostasis, senses changes in the intracellular AMP/ATP ratio and extensively participates in the regulation of glucose metabolism, lipid metabolism, amino acid metabolism, and autophagy. In the field of oncology, the role of AMPK is controversial. Initially, because it is associated with liver kinase B1 (LKB1) and exhibits growth‑suppressive effects, AMPK was considered a tumor suppressor. However, recent studies across various cancer types have clearly demonstrated that AMPK possesses pro‑survival activity, thereby promoting tumor progression, particularly under tumor‑associated stress conditions such as hypoxia, nutrient deprivation, and oxidative stress. This review systematically describes the dual role of AMPK in cancer metabolic reprogramming, summarizes the research progress of AMPK‑targeted cancer therapeutic strategies, and discusses the current challenges and future directions, aiming to provide a theoretical reference for optimizing AMPK‑targeted cancer metabolic therapy.

Keywords:  AMPK; Metabolic reprogramming; Tumor; Warburg effect

DOI:  https://doi.org/10.1007/s11033-026-12577-1
Biomedicines. 2026 Aug 20. pii: 1864. [Epub ahead of print]14(8):

Challenges of Biomarker Application in Patients with Cardiorenal Syndrome.

Elina Khattab, Sotiris Kyriakou, Dimitris Karelas, Maria Ioannou, Evangelos Tatsis, Panagiotis Bouzios, Andreas Mitsis, Constantinos H Papadopoulos, Nikolaos P E Kadoglou.

  Background/Objectives: Cardiorenal syndrome (CRS) is associated with substantially higher morbidity and mortality than either isolated cardiac or renal dysfunction. The application of classical and novel biomarkers has been tested in prompt diagnosis and monitoring of patients with CRS. Methods: This is a comprehensive literature review following a structured approach. We searched MEDLINE and Embase databases from January 2000 to December 2025. Results: The pathophysiology of CRS is complex, and the present review attempts to shed light on the clinical interpretation of the most widely used biomarkers as indices of diagnosis and prognosis. Among them, troponin is elevated in CRS and its absolute levels retain prognostic value, while changes in its levels over time may assist in the diagnosis of acute coronary syndrome. Natriuretic peptides are highly influenced by coexistence of chronic kidney disease (CKD) and in this context have considerable diagnostic and prognostic value. The combination of cystatin C, a biomarker of renal dysfunction, with cardiac biomarkers may create a powerful risk algorithm. Most recently, gene profiling and proteomics have the potential to stratify patients with CRS; however, more data from large cohorts are required for their validation. The therapeutic modulation of biomarkers in CRS patients may help elucidate the underlying pathophysiologic mechanisms. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have emerged as first-line therapy for patients with CRS, despite the fact their mechanisms are mostly unknown. Significant changes in the aforementioned biomarkers and the inflammatory factors may explain their emerging beneficial effects on both heart failure and CKD. Conclusions: The use of biomarkers has increased rapidly in recent years for diagnosis, surveillance and prognostic stratification in CRS.

Keywords:  cardiorenal syndrome; cystatin C; interleukins; natriuretic peptides; sodium-glucose cotransporter-2 inhibitors (SGLT2i); troponin

DOI:  https://doi.org/10.3390/biomedicines14081864
Int J Mol Sci. 2026 Aug 19. pii: 7420. [Epub ahead of print]27(16):

Regulatory Roles of Kaempferol on the PI3K/AKT/mTOR Signaling Pathway and Associated MicroRNAs in Different Cancer Types.

Önder Yumrutaş, Miguel Rios, Pınar Yumrutaş, Murat Korkmaz, Jorge Escobar, Ali Parlar, Jose L Martínez.

  Kaempferol, a naturally occurring dietary flavonoid abundantly found in various fruits and vegetables, has garnered significant attention due to its diverse pharmacological properties, most notably its potent anticancer activity. In the orchestration of cancer pathogenesis, the PTEN/PI3K/AKT/mTOR signaling cascade plays a pivotal role, where aberrant activation or dysregulation of this pathway drastically accelerates tumor cell proliferation, survival, and metabolic reprogramming, thereby driving tumorigenesis. Moreover, non-coding microRNAs (miRNAs) have emerged as key modulators involved in regulating this pathway, functioning as either oncogenes or tumor suppressors to determine cancer cell fate. Previous studies have demonstrated that kaempferol and its derivatives, owing to their molecular structures, suppress the PI3K/AKT/mTOR signaling pathway either directly or indirectly, thereby playing a critical role in inhibiting cancer cell proliferation. Hence, this comprehensive review elucidates the therapeutic potential of kaempferol and its derivatives, focusing specifically on their molecular mechanisms in modulating the PTEN/PI3K/AKT/mTOR pathway. Furthermore, this review highlights the crosstalk between kaempferol and the specific miRNAs targeting these signaling components in various cancer types.

Keywords:  PI3K/AKT/mTOR; anticancer; bioactivity; cancer; kaempferol; miRNA

DOI:  https://doi.org/10.3390/ijms27167420