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Editor’s Choice articles are based on recommendations by the scientific editors of MDPI journals from around the world. Editors select a small number of articles recently published in the journal that they believe will be particularly interesting to readers, or important in the respective research area. The aim is to provide a snapshot of some of the most exciting work published in the various research areas of the journal.

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22 pages, 2522 KB

Open AccessEditor’s ChoiceArticle

Oncological Safety of High Hydrostatic Pressure Treatment: Effects on Cancer-Associated Fibroblast-like Transdifferentiation of Adipose Stromal Cells

by Julia Kristin Brach, Vivica Freiin Grote, Anika Jonitz-Heincke, Rainer Bader, Daniel Strüder, Marco Hoffmann, Sven Gerlach, Petra Fischer, Markus Wirth, Tim Ruhl, Justus P. Beier, Agmal Scherzad and Stephan Hackenberg

Curr. Issues Mol. Biol. 2026, 48(1), 91; https://doi.org/10.3390/cimb48010091 - 16 Jan 2026

Viewed by 280

Abstract

Oncological safety is essential for autologous reconstruction after resection of cartilage-infiltrating head and neck tumors. High hydrostatic pressure (HHP) enables complete devitalization of tumor-infiltrated tissue while preserving extracellular matrix integrity. However, residual soluble tumor-derived products may influence infiltrating stromal cells. This study examined whether conditioned media (CM) from HHP-treated head and neck squamous cell carcinoma (HNSCC) cells induce cancer-associated fibroblast (CAF)-like transdifferentiation of human adipose stromal cells (hASCs). HASCs were exposed to CM from untreated or HHP-treated (300 MPa) HNSCC cells, tumor-CM (TCM), or TGF-β1. Morphological changes in hASCs were evaluated, and CAF marker expression was analyzed by qRT-PCR, immunofluorescence, Western blot, and ELISA. Cytokines were quantified via multiplex analysis. TGF-β1 induced a CAF-like phenotype with α-SMA upregulation, whereas TCM and 0 MPa-CM caused only modest increases in selected markers. Although 300 MPa-CM did not induce CAF-associated molecular signatures, hASCs exhibited morphological alterations, underscoring that morphology alone is insufficient to define CAF transdifferentiation. Cytokine secretion was elevated in response to all CM conditions. These findings indicate that HHP treatment at 300 MPa abolishes the paracrine CAF-inducing potential of tumor-derived mediators in vitro, supporting the oncological safety of HHP-treated tissues under these experimental condition, although further in vivo validation is warranted Full article

(This article belongs to the Section Molecular Medicine)

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16 pages, 1175 KB

Open AccessEditor’s ChoiceArticle

HERVs and Epigenetic Regulators Transcriptional Expression After Chondrogenic Differentiation of Adipose Tissue-Derived Mesenchymal Stem Cells

by Ilaria Galliano, Cristina Calvi, Stefano Gambarino, Alice Dato, Anna Pau, Maddalena Dini, Anna Clemente, Carlotta Castagnoli and Massimiliano Bergallo

Curr. Issues Mol. Biol. 2026, 48(1), 37; https://doi.org/10.3390/cimb48010037 - 26 Dec 2025

Viewed by 297

Abstract

Mesenchymal stem cells (MSCs) are multipotent cells capable of differentiating into various connective tissue cell types. Adipose tissue provides a rich source of MSCs (ADSCs), which can differentiate into osteoblasts, adipocytes, and chondroblasts. Pluripotency factors such as SOX2, NANOG, and OCT4 maintain MSC stemness, whereas human endogenous retroviruses (HERVs) and their epigenetic regulators TRIM28 and SETDB1 have been implicated in transcriptional regulation and cell fate decisions. This study investigated the transcriptional expression of HERV-H, -K, and -W, TRIM28, SETDB1, and pluripotency markers (NANOG, OCT4, SOX2) during chondrogenic differentiation of ADSCs using Real-Time PCR. Chondrogenesis was confirmed by aggrecan (ACAN) upregulation and aggrecan immunostaining. Although no statistically significant differences were observed for HERV-H, HERV-K, or HERV-W, HERV-K and HERV-W showed a trend toward decreased expression in differentiated cells, consistent with the overall shift in transcriptional profile during lineage commitment. TRIM28 expression was significantly reduced, while SETDB1 showed a decreasing trend. Among pluripotency markers, OCT4 was significantly downregulated, whereas NANOG and SOX2 remained stable. Correlation analyses revealed that in differentiated ADSCs, HERV-W expression correlated negatively with TRIM28 and positively with SETDB1, while no correlations were found for HERV-H or HERV-K. These findings suggest that specific HERV families and their epigenetic regulators may undergo coordinated modulation during chondrogenic differentiation, supporting a complex and family-specific interplay between retroelement regulation, pluripotency factors, and MSC lineage commitment. Full article

(This article belongs to the Special Issue Innovative Approaches in Bone and Cartilage Regeneration: From Stem Cells to Organoids)

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19 pages, 5171 KB

Open AccessEditor’s ChoiceArticle

Interferon-Type-I Response and Autophagy Independently Regulate Radiation-Induced HLA-Class-I Molecule Expression in Lung Cancer

by Erasmia T. Xanthopoulou, Ioannis Lamprou, Ioannis M. Koukourakis, Achilleas G. Mitrakas, Georgios D. Michos, Anastasia Polyzoidou, Filippos G. Antoniadis, Alexandra Giatromanolaki and Michael I. Koukourakis

Curr. Issues Mol. Biol. 2026, 48(1), 28; https://doi.org/10.3390/cimb48010028 - 25 Dec 2025

Viewed by 425

Abstract

Background/Objectives: The enhancement of antitumor immune responses by radiotherapy (RT) is partially attributed to the activation of the IFN-type-I pathway. However, the loss of HLA-class-I molecules, which occurs in a large percentage of non-small-cell lung cancers (NSCLCs), may block the cytotoxic effect of T-cells and immunotherapy (IO). Moreover, autophagy is also involved in HLA downregulation. We investigated the complex interactions between RT, HLA molecules, autophagy, and IFN-type-I responses. Methods: The A549, H1299, and ATG7-deficient NSCLC cell lines, along with the modified shLC3A H1299 cell line, were used for in vitro experiments. The effect of RT (8 and 3 × 8 Gy) on Interferon beta (IFNβ), IFN-stimulated genes (ISGs), and HLA-class-I expression in combination with IFN-type-I-response inhibitors (Ruxolitinib, Tofacitinib, Amlexanox) targeting the JAK and TBK1 was studied with Flow cytometry and RT-PCR. Results: RT significantly induced HLA-class-I expression. A parallel upregulation of IFNβ and ISGs mRNA levels was also documented. Although the IFN-type-I-response inhibitors suppressed the RT-induced IFNβ and ISGs expression, their effect on HLA-class-I expression was minimal. Blockage of LC3A autophagy (shLC3A cell line) significantly upregulated HLA-class-I basal levels, and RT further enhanced HLA expression. IFN-type-I-response inhibitors blocked the RT-inductive effect in the shLC3A H1299, but had no effect in the ATG7-deficient H1650 cell line. Conclusions: The current study supports the theory that baseline autophagy, RT-induced autophagy blockage, and IFN-type-I response enhancement define the HLA-class-I levels in NSCLC cells. This complex interplay emerges as a promising target for the development of radio-vaccination strategies to enhance the efficacy of radio-immunotherapy. Full article

(This article belongs to the Special Issue Molecular Insights into Radiation Oncology)

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22 pages, 1830 KB

Open AccessEditor’s ChoiceArticle

β-Arrestin 1 Differentially Modulates cAMP and ERK Pathways Downstream of the FSH Receptor

by Sei Hyun Park, Munkhzaya Byambaragchaa, Ye Rin Yu, Jae Won Lee, Min-Jeong Kwak, Seung-Bin Yoon, Ji-Su Kim, Myung-Hwa Kang and Kwan-Sik Min

Curr. Issues Mol. Biol. 2025, 47(12), 1051; https://doi.org/10.3390/cimb47121051 - 16 Dec 2025

Viewed by 402

Abstract

This study compared the gonadotropin gene sequences (LH and FSH subunits) of Cynomolgus and Rhesus monkeys and produced recombinant single-chain LHβ/α and FSHβ/α proteins. The α- and FSHβ-subunit sequences were identical between species, while LHβ showed only minor synonymous differences. The recombinant hormones were successfully expressed and shown to be mainly N-glycosylated. Recombinant monkey FSHβ/α activated cAMP signaling in human FSH receptor-expressing cells, confirming its biological activity. β-arrestin 1 was found to have dual roles: its absence increased cAMP signaling (negative regulation), but it was required for ERK1/2 activation. ERK activation depended mainly on the cAMP/PKA pathway. Human and rat FSH receptors displayed different ERK activation timing, indicating species-specific signaling behavior. Overall, the study establishes a reliable system for producing functional recombinant monkey gonadotropins and clarifies how β-arrestin 1 differentially regulates FSH receptor signaling. Full article

(This article belongs to the Collection Advancements in Molecular Biology and Pharmaceutical Science)

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14 pages, 741 KB

Open AccessEditor’s ChoiceReview

Mitochondrial Dysfunction and Metabolic Reprogramming in Chronic Inflammatory Diseases: Molecular Insights and Therapeutic Opportunities

by Mi Eun Kim, Yeeun Lim and Jun Sik Lee

Curr. Issues Mol. Biol. 2025, 47(12), 1042; https://doi.org/10.3390/cimb47121042 - 14 Dec 2025

Cited by 2 | Viewed by 1679

Abstract

Chronic inflammatory diseases are driven by persistent immune activation and metabolic imbalance that disrupt tissue homeostasis. Mitochondrial dysfunction disrupts cellular bioenergetics and immune regulation, driving persistent inflammatory signaling. Mitochondrial dysfunction, characterized by excessive production of ROS, release of mitochondrial DNA, and defective mitophagy, amplifies inflammatory signaling and contributes to disease progression. Meanwhile, metabolic reprogramming in immune and stromal cells establishes distinct bioenergetic profiles. These profiles maintain either pro-inflammatory or anti-inflammatory phenotypes through key signaling regulators such as HIF-1α, AMPK, mTOR, and SIRT3. Crosstalk between mitochondrial and metabolic pathways determines whether inflammation persists or resolves. Recent advances have identified critical molecular regulators, including the NRF2–KEAP1 antioxidant system, the cGAS–STING innate immune pathway, and the PINK1–Parkin mitophagy pathway, as potential therapeutic targets. Pharmacologic modulation of metabolic checkpoints and restoration of mitochondrial homeostasis represent key strategies for re-establishing cellular homeostasis. Developing approaches, including NAD⁺ supplementation, mitochondrial transplantation, and gene-based interventions, also show significant therapeutic potential. This review provides a mechanistic synthesis of how mitochondrial dysfunction and metabolic reprogramming cooperate to maintain chronic inflammation and highlights molecular pathways that represent promising targets for precision therapeutics in inflammatory diseases. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Innovative Therapeutic Approaches in Inflammatory Diseases, Pioneering Precision Medicine Solutions)

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14 pages, 2214 KB

Open AccessEditor’s ChoiceArticle

Evaluation of the Role of AID-Induced Mutagenesis in Resistance to B-Cell Receptor Pathway Inhibitors in Chronic Lymphocytic Leukemia

by Chiara Pighi, Alessandro Gasparetto, Elisa Genuardi, Jianli Tao, Qi Wang, Candida Vitale, Valentina Griggio, Rocco Piazza, Sabino Ciavarella, Marta Coscia, Simone Ferrero, Alberto Zamò, Claudia Voena and Roberto Chiarle

Curr. Issues Mol. Biol. 2025, 47(12), 1031; https://doi.org/10.3390/cimb47121031 - 10 Dec 2025

Viewed by 524

Abstract

Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries, and B-cell receptor (BCR) pathway inhibitors such as idelalisib and ibrutinib are currently established therapies for CLL. Although effective, these drugs frequently lead to resistance, but the mechanisms are still not fully understood. Activation-induced cytidine deaminase (AID) is a B-cell enzyme essential for antibody diversification. However, it can also introduce off-target mutations, leading to genomic instability. This study investigates whether treatment with BCR pathway inhibitors increases AID activity in CLL and whether this activity contributes to the development of drug resistance. Peripheral blood samples from CLL patients were collected before and after treatment with idelalisib or ibrutinib. Targeted sequencing was used to identify mutations in known AID off-target genes. Concurrently, AID-wild type (AID-WT) and AID-knockout (AID-KO) CLL cell lines were established and subsequently exposed to escalating doses of BCR pathway inhibitors to develop drug-resistant models. In patient samples, treatment with BCR pathway inhibitors was associated with an increase in AID-dependent mutations in off-target genes, including BCL2, MYC, and IRF8. The in vitro models efficiently recapitulated the patients’ data, as only AID-WT CLL cells accumulated mutations in the same AID off-target genes after drug exposure. However, no mutations were detected in genes that could mediate drug resistance. We conclude that BCR pathway inhibitors enhance AID mutational activity in CLL, but this does not appear to be directly involved in driving drug resistance. AID-targeted loci may nonetheless serve as biomarkers for monitoring genomic instability during treatment and inform further study. Full article

(This article belongs to the Section Molecular Medicine)

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