https://doi.org/10.1172/jci.insight.

Here, Tobias B. Huber & team use a state-of-the-art, tour de force experimental design to show LSD1 regulates kidney development, and its dysfunction disrupts key kidney cells, leading to cyst formation in mouse and organoid models.

The image shows severe structural changes in the adult mouse kidney with loss of KDM1a. Nephrology.

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⁴Faculty of Biology, Albert Ludwigs University of Freiburg, Freiburg, Germany.

⁵Institute of Medical Bioinformatics and Systems Medicine and.

⁶Institute of Surgical Pathology, Faculty of Medicine, Medical Center — University of Freiburg, Freiburg, Germany.

Year 2025 This could essentially end disease where the diseases would be edited off and the host repaired internally.

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Scientists identified 473 human genes that act as genetic “on/off switches,” shaping disease risk through tissue-specific or universal patterns regulated by DNA changes and hormones.

Study: Switch-like gene expression modulates disease risk. Image Credit: gopixa / Shutterstock.

In a recent article published in Nature Communications, researchers analyzed methylomes, transcriptomes, and genomes from 943 individuals to characterize and identify genes that exhibit distinct on-off switches and explore their epigenetic and genetic regulation.

Nutrient stress in DNA damage.

The dynamic interplay between nutrient stress and DNA damage governs cellular survival through coordinated regulation of genomic integrity and metabolic adaptation. Nutrient deprivation, such as glucose or amino acid limitation, engages nutrient sensors, including AMPK and mTORC1, to rewire energy homeostasis while directly influencing DNA repair via regulating PARP1, BRCA1, and other core repair machinery.

DNA damage-activated kinases (ATM/ ATR) orchestrate metabolic reprogramming to fuel repair processes, enforcing context-dependent cell fate decisions via cell cycle arrest or apoptosis regulation.

Nutrient stress exacerbates genomic instability through depleting antioxidants, such as NADPH or glutathione (GSH), promoting oxidative DNA lesions that overwhelm repair capacity, while defective DNA repair conversely drives metabolic dysregulation in tumors.

In the future, more efficacious tumor therapeutic strategies propose combining targeted nutrient stress with DNA damage repair inhibitors to exploit synthetic lethality. However, clinical translation requires resolving key challenges including tumor heterogeneity in nutrient stress-response pathways and adaptive metabolic plasticity during therapy sciencenewshighlights ScienceMission https://sciencemission.com/nutrient-stress–and-DNA-damage

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Cells are constantly exposed to various stresses, including nutrient deprivation and genotoxic stress, which dynamically interact with cellular sensing pathways to influence metabolism, gene expression, and homeostasis. The integration of nutrient-sensing mechanisms and DNA damage response pathways is critical in cancer progression. While individual processes are well-characterized, their cross-regulatory mechanisms are just beginning to emerge. Deciphering the interplay between nutrient stress and DNA damage is crucial for elucidating the mechanisms underlying cellular responses to stress and developing therapeutic strategies for various diseases, including cancer. This review highlights the relationship between nutrient stress and DNA damage, especially its underlying sensing pathway and cell fate determination.

Microscopic images of human tissue are a cornerstone of biomedical research and clinical diagnostics. Yet despite their importance, these images often remain difficult to analyze systematically and to connect with other types of biological data. A new study led by CeMM Principal Investigator André Rendeiro and published in Nature Methods introduces “LazySlide,” an open-source software tool that brings the power of foundation models and aims to democratize digital pathology analysis.

Whether it’s an inflamed artery, a tumor spreading into the lung or subtle damage in an organ, when doctors or researchers want to understand what’s happening inside a tissue, one of the most trusted tools is still the microscope. Today, they have largely gone digital: A single tissue sample can be scanned into a whole-slide image so detailed that one can zoom from a bird’s-eye view of the entire tissue down to individual cells. These images, therefore, contain enormous information about tissues from different scales.

However, these images are huge, complex, and often difficult to analyze in a modern, data-driven way. While genetics and single-cell biology have developed effective ways for sharing and comparing data, digital pathology images are hard to incorporate—stored in proprietary formats, processed with incompatible tools, and hard to connect to molecular information like RNA sequencing. Thus, the valuable resources of digitalized tissue images are largely underutilized in many research and clinical settings.

PARG inhibition potentiates the efficacy of chemotherapy and PD-1 blockade in murine cholangiocellular carcinoma models.

PARG (poly(ADP-ribose) glycohydrolase) plays a key role in cancer cells by regulating poly(ADP-ribose) turnover and DNA damage responses, thereby supporting genomic stability, transcriptional programs, and survival pathways that enable tumour growth and treatment resistance. Yu, Xie, Yu, Zhao, Xu, Yang, Wei and coworkers evaluated the role of PARG in the development, progression and resistance to therapy in cholangiocarcinoma. In a cohort of 275 patients with cholangiocellular carcinoma (CCA), they observed that the levels of PARG are hyperactivated in the tumour tissue, and higher levels of PARG are associated with worse prognosis. Pharmacological or genetic inhibition of PARG in murine CCA models suppresses tumour growth by activating the Hippo pathway, leading to YAP/TAZ inactivation and reduced proliferative and stemness programs in cholangiocarcinoma cells. Notably, PARG inhibition synergizes with standard chemotherapy and enhances responsiveness to immunotherapy in mice, suggesting a role in modulating tumour cell–intrinsic survival pathways and the tumour immune microenvironment. Key open questions include the safety and specificity of sustained PARG inhibition in chronic liver disease and whether Hippo pathway activation and immune sensitization observed in models will translate into durable clinical benefit in heterogeneous human tumours.

Full text here: https://www.journal-of-hepatology.eu/article/S0168-8278(…0/fulltext.

EASL — the home of hepatology.

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Cholangiocarcinoma (CCA) is a lethal malignancy with limited therapeutic options. We investigated the oncogenic role of poly(ADP-ribose) glycohydrolase (PARG) and evaluated potential therapeutic strategies.