02014nas a2200229   4500000000100000000000100001008004100002260001500043653002200058653001700080100001400097700001800111700002000129700002400149700003000173245006900203856005500272300001000327490000700337520142600344022001401770       2025                            d  c2025-04-1110aBiological models10aCell biology1 aYuki Ueda1 aSatoshi Omiya1 aJonathan Pinney1 aMichelle A. Bylicky1 aMolykutty J. Aryankalayil00aLiver quad culture chip as a model for radiation injury research  uhttps://www.nature.com/articles/s41598-025-96140-1  a124140 v153 aBoth cancer patients receiving radiotherapy and civilians in a mass casualty nuclear event may suffer from radiation induced damage to organ systems. Radiation induced liver disease (RILD) can cause acute and long-term organ dysfunction that potentially leads to death. The objective of this study was to ascertain the validity of a liver quad-culture chip, a micro-physiological system comprising primary human hepatocytes and non-parenchymal cells (NPCs), including liver sinusoidal endothelial cells, hepatic stellate cells (HSCs), and Kupffer cells, as a model for RILD. The radiation exposure to the chip model resulted in DNA damage and cellular senescence of hepatocytes and NPCs. We observed metabolic dysfunction, inflammation, endothelial dysfunction, and HSCs activation. Whole genome sequencing revealed gene alterations in pathways relevant to RILD, as well as the potential efficacy of N-acetylcysteine amide (NACA) against RILD. NACA exhibited the capacity to mitigate DNA damage and cellular senescence and decreased the impact of radiation exposure on other pathophysiological changes. CDKN1A and miR-34a-5p were validated as useful radiation response and treatment efficacy biomarkers. These findings highlight the potential of the liver quad-culture chip as an effective model for investigating the microenvironment in RILD and for evaluating the efficacy of therapeutic countermeasures and biomarkers.  a2045-2322