Obesity promotes a range of associated conditions, including hearing impairment; however, mechanisms are lacking. Self-evidently, an insult on any cellular constituent of the auditory organ can disrupt hearing. Here, using the mouse auditory cell line, HEI-OC1, we provide insights into adipose-associated ototoxicity. Adipose extracts from mice with obesity, diet- or genetically induced, suppress HEI-OC1's survival and ATP generation. Proteomic profiling shows an upregulation of the inflammatory response pathway and proteins such as Podoplanin and Low-density lipoprotein receptor. Likewise, the Programmed cell death 4 (PDCD4) protein was induced. These results correspond to a downregulation of glycolysis and oxidative phosphorylation but an upregulation of the G2/M checkpoint. Additionally, pathways such as IL6-JAK-STAT3, IL2-STAT5, interferon gamma response, cholesterol response, bile acid metabolism, RAS, Apoptosis, and TGF-β were upregulated. Furthermore, the adipose extracts cause cellular morphological changes consistent with cells under stress. Functional assays point to alterations in levels of proteins related to calcium and ER homeostasis/stress. The ER-resident protein SARAF, an inhibitor of calcium overfilling, is among the proteins markedly downregulated. GRP78 protein levels increased, suggesting ER/calcium stress. Finally, Thapsigargin impairs HEI-OC1 survival, reminiscent of the effect of the adipose tissue extracts. Our analyses warrant further exploration of inflammation and ER/calcium stress in connection to obesity-associated ototoxicity.
© 2025. The Author(s).

Neurons are almost exclusively cultured in media containing glucose at much higher concentrations than found in the brain. To test whether these "standard" hyperglycemic culture conditions affect neuronal respiration relative to near-euglycemic conditions, we compared neuronal cultures grown with minimal glial contamination from the hippocampus and cortex of neonatal C57BL/6NCrl mice in standard commercially available media (25 mM Glucose) and in identical media with 5 mM glucose. Neuronal growth in both glucose concentrations proceeded until at least 14 days in vitro, with similar morphology and synaptogenesis. Neurons grown in high glucose were highly dependent on glycolysis as their primary source of ATP, measured using ATP luminescence and cellular respirometry assays. In contrast, neurons grown in 5 mM glucose showed a more balanced dependence on glycolysis and mitochondrial oxidative phosphorylation (OXPHOS), greater reserve mitochondrial respiration capacity, and increased mitochondrial population relative to standard media. Our results show that neurons cultured in artificially high glucose-containing media preferentially use glycolysis, opposite to what is known for neurons in vivo as the primary pathway for ATP maintenance. Changes in gene and protein expression levels corroborate these changes in function and additionally suggest that high glucose culture media increases neuronal inflammation. We suggest using neuronal culture systems in 5 mM glucose to better represent physiologically relevant neuronal respiration.
© 2025 The Author(s). Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.

This study addresses the urgent need for effective therapies for patients with brain metastases from cutaneous melanoma, a major cause of treatment failure despite recent therapeutic advances. Utilizing mouse models that mimic human melanoma brain metastases, this study investigates the necessity of focal adhesion kinase (FAK) in the development of distant metastases and its potential as a therapeutic target. Pharmacological inhibition of FAK demonstrates significant efficacy in reducing the development of brain metastases in preclinical mouse models. Importantly, the study provides insight into the crosstalk between FAK and mitogen-activated protein kinase (MAPK) pathway signaling and highlights the synergistic effects of combined inhibition of FAK, rapidly accelerated fibrosarcoma (RAF), and mitogen-activated protein kinase kinase (MEK) in cutaneous melanoma. These findings provide the rationale for clinical evaluation of the efficacy of the FAK inhibitor defactinib and the RAF/MEK inhibitor avutometinib in patients with brain metastases from cutaneous melanoma.
Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.

G protein-coupled receptors (GPCRs) modulate the function of adipose tissue (AT) in general and of adipocytes, specifically. Although it is well-established that GPCRs are widely expressed in AT, their repertoire as well as their regulation and function in (patho)physiological conditions (e.g., obesity) is not fully resolved. Here, we established FATTLAS, an interactive public database, for improved access and analysis of RNA-seq data of mouse and human AT. After extracting the GPCRome of non-obese and obese individuals, highly expressed and differentially regulated GPCRs were identified. Exemplarily, we describe four receptors (GPR146, MRGPRF, FZD5, PTGER2) and analyzed their functions in a (pre)adipocyte cell model. Besides all receptors being involved in adipogenesis, MRGPRF is essential for adipocyte viability and regulates cAMP levels, while GPR146 modulates adipocyte lipolysis via constitutive activation of Gi proteins. Taken together, by implementing and using FATTLAS we describe four hitherto unrecognized GPCRs associated with AT function and adipogenesis.
© 2023 The Author(s).

FBXO28 is a member of F-box proteins that are the substrate receptors of SCF (SKP1, CULLIN1, F-box protein) ubiquitin ligase complexes. Despite the implications of its role in cancer, the function of FBXO28 in epithelial-mesenchymal transition (EMT) process and metastasis for cancer remains largely unknown. Here, we report that FBXO28 is a critical negative regulator of migration, invasion and metastasis in human hepatocellular carcinoma (HCC) in vitro and in vivo. FBXO28 expression is upregulated in human epithelial cancer cell lines relative to mesenchymal counterparts. Mechanistically, by directly binding to SNAI2, FBXO28 functions as an E3 ubiquitin ligase that targets the substrate for degradation via ubiquitin proteasome system. Importantly, we establish a cooperative function for PKA in FBXO28-mediated SNAI2 degradation. In clinical HCC specimens, FBXO28 protein levels positively whereas negatively correlate with PKAα and SNAI2 levels, respectively. Low FBXO28 or PRKACA expression is associated with poor prognosis of HCC patients. Together, these findings elucidate the novel function of FBXO28 as a critical inhibitor of EMT and metastasis in cancer and provide a mechanistic rationale for its candidacy as a new prognostic marker and/or therapeutic target in human aggressive HCC.
© 2023. The Author(s).