Depletion of proteasome subunit PSMD1 induces cancer cell death via protein ubiquitination and DNA damage, irrespective of p53 status.

Hepatocellular carcinoma (HCC) is characterized by high incidence and fatality rates worldwide. In our exploration of prognostic factors in HCC, the 26s proteasome subunit, non-ATPase 1 (PSMD1) protein emerged as a significant contributor, demonstrating its potential as a therapeutic target in this aggressive cancer. PSMD1 is a subunit of the 19S regulatory particle in the 26S proteasome complex; the 19S particle controls the deubiquitination of ubiquitinated proteins, which are then degraded by the proteolytic activity of the complex. Proteasome-targeting in cancer therapy has received significant attention because of its practical application as an established anticancer agent. We investigated whether PSMD1 plays a critical role in cancer owing to its prognostic significance. PSMD1 depletion induced cell cycle arrest in G2/M phase, DNA damage and apoptosis of cancer cells, irrespective of the p53 status. PSMD1 depletion-mediated cell death was accompanied by an increase in overall protein ubiquitination. These phenotypes occurred exclusively in cancer cells, with no effects observed in normal cells. These findings indicate that PSMD1 depletion-mediated ubiquitination of cellular proteins induces cell cycle arrest and eventual death in cancer cells, emphasizing PSMD1 as a potential therapeutic target in HCC.

CXCL10 upregulation in radiation-exposed human peripheral blood mononuclear cells as a candidate biomarker for rapid triage after radiation exposure.

PURPOSE: In case of a nuclear accident, individuals with high-dose radiation exposure (>1-2 Gy) should be rapidly identified. While ferredoxin reductase (FDXR) was recently suggested as a radiation-responsive gene, the use of a single gene biomarker limits radiation dose assessment. To overcome this limitation, we sought to identify reliable radiation-responsive gene biomarkers. MATERIALS AND METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from mice after total body irradiation, and gene expression was analyzed using a microarray approach to identify radiation-responsive genes. RESULTS: In light of the essential role of the immune response following radiation exposure, we selected several immune-related candidate genes upregulated by radiation exposure in both mouse and human PBMCs. In particular, the expression of ACOD1 and CXCL10 increased in a radiation dose-dependent manner, while remaining unchanged following lipopolysaccharide (LPS) stimulation in human PBMCs. The expression of both genes was further evaluated in the blood of cancer patients before and after radiotherapy. CXCL10 expression exhibited a distinct increase after radiotherapy and was positively correlated with FDXR expression. CONCLUSIONS: CXCL10 expression in irradiated PBMCs represents a potential biomarker for radiation exposure.

Increased Screening Rates for Thyroid Cancer Among Residents Living Near Nuclear Power Plants.

Frequent screening for thyroid cancer has been suggested as a probable explanation for the observed high risk of thyroid cancer in nuclear power plant (NPP) areas. We aimed to compare thyroid cancer screening rates of residents living near NPPs to those of the general population. This study utilized data from two national survey-based studies in 2016 and in 2014, respectively, for residents (n = 1,200) living in administrative districts within 5 km of NPP sites as the interest group, and the general population (n = 228,712) including distant-living residents (n = 19,100) in administrative districts within 30 km of NPP sites as reference groups. We observed an increase in screening rates in residents near NPPs, which may lead to a higher possibility of thyroid cancer detection. Therefore, further epidemiological studies investigating radiation-induced thyroid cancer risk among residents near NPPs should be carefully designed and interpreted considering possible detection bias.

Organ dose reconstruction for the radiation epidemiological study of Korean radiation workers: the first dose evaluation for the Korean Radiation Worker Study (KRWS).

The Korea Institute of Radiological and Medical Sciences has started a radiation epidemiological study, titled "Korean Radiation Worker Study," to evaluate the health effects of occupational exposure to radiation. As a part of this study, we investigated the methodologies and results of reconstructing organ-specific absorbed doses based on personal dose equivalent, Hp(10), reported from 1984 to 2019 for 20,605 Korean radiation workers. For the organ dose reconstruction, representative exposure scenarios (i.e., radiation energy and exposure geometry) were first determined according to occupational groups, and dose coefficients for converting Hp(10) to organ absorbed doses were then appropriately taken based on the exposure scenarios. Individual annual doses and individual cumulative doses were reconstructed for 27 organs, and the highest values were observed in the thyroid doses (on average 0.77 mGy/y and 10.47 mGy, respectively). Mean values of individual cumulative absorbed doses for the red bone marrow, colon, and lungs were 7.83, 8.78, and 8.43 mSv, respectively. Most of the organ doses were maximum for industrial radiographers, followed by nuclear power plant workers, medical workers, and other facility workers. The organ dose database established in this study will be utilized for organ-specific risk estimation in the Korean Radiation Worker Study.

The miR-126-5p and miR-212-3p in the extracellular vesicles activate monocytes in the early stage of radiation-induced vascular inflammation implicated in atherosclerosis.

People exposed to radiation in cancer therapy and nuclear accidents are at increased risk of cardiovascular outcomes in long-term survivors. Extracellular vesicles (EVs) are involved in radiation-induced endothelial dysfunction, but their role in the early stage of vascular inflammation after radiation exposure remains to be fully understood. Herein, we demonstrate that endothelial cell-derived EVs containing miRNAs initiate monocyte activation in radiation-induced vascular inflammation. In vitro co-culture and in vivo experimental data showed that endothelial EVs can be sensitively increased by radiation exposure in a dose-dependent manner, and stimulate monocytes releasing monocytic EVs and adhesion to endothelial cells together with an increase in the expression of genes encoding specific ligands for cell-cell interaction. Small RNA sequencing and transfection using mimics and inhibitors explained that miR-126-5p and miR-212-3p enriched in endothelial EVs initiate vascular inflammation by monocyte activation after radiation exposure. Moreover, miR-126-5p could be detected in the circulating endothelial EVs of radiation-induced atherosclerosis model mice, which was found to be tightly correlated with the atherogenic index of plasma. In summary, our study showed that miR-126-5p and miR-212-3p present in the endothelial EVs mediate the inflammatory signals to activate monocytes in radiation-induced vascular injury. A better understanding of the circulating endothelial EVs content can promote their use as diagnostic and prognostic biomarkers for atherosclerosis after radiation exposure.

StemRegenin 1 Mitigates Radiation-Mediated Hematopoietic Injury by Modulating Radioresponse of Hematopoietic Stem/Progenitor Cells.

Hematopoietic injury resulting from the damage of hematopoietic stem/progenitor cells (HSPCs) can be induced by either nuclear accident or radiotherapy. Radiomitigation of HSPCs is critical for the development of medical countermeasure agents. StemRegenin 1 (SR1) modulates the maintenance and function of HSPCs under non-stress conditions. However, the impact of SR1 in radiation-induced hematopoietic injury both in vivo and in vitro remains unknown. In this study, we found that treatment with SR1 after irradiation of C57BL/6 mice significantly mitigates TBI-induced death (80% of SR1-treated mice survival vs. 30% of saline-treated mice survival) with enhanced recovery of peripheral blood cell counts, with the density and cell proliferation of bone marrow components as observed by Hematoxylin and Eosin (H&E) and Ki-67 staining. Interestingly, in vitro analysis of human HSPCs showed that SR1 enhanced the population of human HSPCs (CD34+) under both non-irradiating and irradiating conditions, and reduced radiation-induced DNA damage and apoptosis. Furthermore, SR1 attenuated the radiation-induced expression of a member of the pro-apoptotic BCL-2 family and activity of caspase-3. Overall, these results suggested that SR1 modulates the radioresponse of HSPCs and might provide a potential radiomitigator of hematopoietic injury, which contributes to increase the survival of patients upon irradiation.

Characteristics and Trends of Occupational Radiation Doses among Korean Radiation Workers (1984-2020).

ABSTRACT: This study identified characteristics of occupational radiation doses among Korean radiation workers from 1984-2020 using the National Dose Registry. The overall mean effective dose from 1984-2020 was 1.05 mSv y -1 , with the highest mean effective dose of 2.61 mSv y -1 for non-destructive testing workers. The mean effective dose gradually decreased from 2.97 mSv in 1984 to 0.34 mSv in 2020. The largest decline ratio between 1984 and 2020 was observed in educational institutions at 97.4% (0.84 mSv in 1984 and 0.02 mSv in 2020), followed by industries at 96.5% (2.55 mSv in 1984 and 0.09 mSv in 2020). Compared to 1984, the individual dose-distribution and collective dose-distribution ratios in 2020 decreased by 82.6-99% and 53.7-94.7%, respectively. This downward trend was consistent in all occupations, while decline characteristics were different depending on occupation types, work experience, and changes in radiation safety regulations. Considering that some changes in radiation doses in the registry could be solely based on changing the recording mode regardless of the actual changes in radiation doses, a careful understanding of radiation doses in the registry is particularly relevant for future epidemiological studies.

ABCA1-Mediated EMT Promotes Papillary Thyroid Cancer Malignancy through the ERK/Fra-1/ZEB1 Pathway.

Papillary thyroid cancer (PTC) is the most prevalent histological type of thyroid cancer (TC) worldwide. Although tumor metastasis occurs in regional lymph nodes, distant metastasis (DM) may also occur. Radioactive iodine (RAI) therapy is an effective treatment for TC; however, resistance to RAI occurs in patients with DM. Therefore, in this study, we investigated the efficacy of DM-related biomarkers as therapeutic targets for PTC therapy. ABCA1 expression was higher in aggressive BCPAP cells than in other PTC cells in terms of migration and invasion capacity. The knockdown of ABCA1 substantially decreased the expression of the epithelial-mesenchymal transition (EMT) marker, N-cadherin, and EMT regulator (ZEB1), resulting in suppressed migration and invasion of BCPAP cells. ABCA1 knockdown also reduced ERK activity and Fra-1 expression, which correlated with the effects of an ERK inhibitor or siRNA-mediated inhibition of ERK or Fra-1 expression. Furthermore, ABCA1-knocked-down BCPAP cells suppressed cell migration and invasion by reducing Fra-1 recruitment to Zeb1 promoter; lung metastasis was not observed in mice injected with ABCA1-knocked-down cells. Overall, our findings suggest that ABCA1 regulates lung metastasis in TC cells.

Combined Administration of Pravastatin and Metformin Attenuates Acute Radiation-Induced Intestinal Injury in Mouse and Minipig Models.

Radiation-induced gastrointestinal (GI) damage is one of the critical factors that serve as basis for the lethality of nuclear accidents or terrorism. Further, there are no Food and Drug Administration-approved agents available to mitigate radiation-induced intestinal injury. Although pravastatin (PS) has been shown to exhibit anti-inflammatory and epithelial reconstructive effects following radiation exposure using mouse and minipig models, the treatment failed to improve the survival rate of high-dose irradiated intestinal injury. Moreover, we previously found that metformin (MF), a common drug used for treating type 2 diabetes mellitus, has a mitigating effect on radiation-induced enteropathy by promoting stem cell properties. In this study, we investigated whether the combined administration of PS and MF could achieve therapeutic effects on acute radiation-induced intestinal injury in mouse and minipig models. We found that the combined treatment markedly increased the survival rate and attenuated histological damage in a radiation-induced intestinal injury mouse model, in addition to epithelial barrier recovery, anti-inflammatory effects, and improved epithelial proliferation with stem cell properties. Furthermore, in minipig models, combined treatment with PS and MF ameliorates gross pathological damage in abdominal organs and attenuated radiation-induced intestinal histological damage. Therefore, the combination of PS and MF effectively alleviated radiation-induced intestinal injury in the mouse and minipig models. We believe that the combined use of PS and MF is a promising therapeutic approach for treating radiation-induced intestinal injury.

NPFFR2 Contributes to the Malignancy of Hepatocellular Carcinoma Development by Activating RhoA/YAP Signaling.

G protein-coupled receptors (GPCRs) are a diverse family of cell surface receptors implicated in various physiological functions, making them common targets for approved drugs. Many GPCRs are abnormally activated in cancers and have emerged as therapeutic targets for cancer. Neuropeptide FF receptor 2 (NPFFR2) is a GPCR that helps regulate pain and modulates the opioid system; however, its function remains unknown in cancers. Here, we found that NPFFR2 is significantly up-regulated in liver cancer and its expression is related to poor prognosis. Silencing of NPFFR2 reduced the malignancy of liver cancer cells by decreasing cell survival, invasion, and migration, while its overexpression increased invasion, migration, and anchorage-independent cell growth. Moreover, we found that the malignant function of NPFFR2 depends on RhoA and YAP signaling. Inhibition of Rho kinase activity completely restored the phenotypes induced by NPFFR2, and RhoA/F-Actin/YAP signaling was controlled by NPFFR2. These findings demonstrate that NPFFR2 may be a potential target for the treatment of hepatocellular carcinoma.

Centella asiatica-Derived Endothelial Paracrine Restores Epithelial Barrier Dysfunction in Radiation-Induced Enteritis.

Radiation-induced enteritis is frequently observed following radiotherapy for cancer or occurs due to radiation exposure in a nuclear accident. The loss of the epithelial integrity leads to 'leaky gut', so recovery of damaged epithelium is an important strategy in therapeutic trials. Centella asiatica (CA), a traditional herbal medicine, is widely used for wound healing by protecting against endothelial damage. In this study, we investigated the radio-mitigating effect of CA, focusing on the crosstalk between endothelial and epithelial cells. CA treatment relieved radiation-induced endothelial dysfunction and mitigated radiation-induced enteritis. In particular, treatment of the conditioned media from CA-treated irradiated endothelial cells recovered radiation-induced epithelial barrier damage. We also determined that epidermal growth factor (EGF) is a critical factor secreted by CA-treated irradiated endothelial cells. Treatment with EGF effectively improved the radiation-induced epithelial barrier dysfunction. We also identified the therapeutic effects of CA-induced endothelial paracrine in a radiation-induced enteritis mouse model with epithelial barrier restoration. Otherwise, CA treatment did not show radioprotective effects on colorectal tumors in vivo. We showed therapeutic effects of CA on radiation-induced enteritis, with the recovery of endothelial and epithelial dysfunction. Thus, our findings suggest that CA is an effective radio-mitigator against radiation-induced enteritis.

Zileuton Alleviates Radiation-Induced Cutaneous Ulcers via Inhibition of Senescence-Associated Secretory Phenotype in Rodents.

Radiation-induced cutaneous ulcers are a challenging medical problem for patients receiving radiation therapy. The inhibition of cell senescence has been suggested as a prospective strategy to prevent radiation ulcers. However, there is no effective treatment for senescent cells in radiation ulcers. In this study, we investigated whether zileuton alleviated radiation-induced cutaneous ulcer by focusing on cell senescence. We demonstrate increased cell senescence and senescence-associated secretory phenotype (SASP) in irradiated dermal fibroblasts and skin tissue. The SASP secreted from senescent cells induces senescence in adjacent cells. In addition, 5-lipoxygenase (5-LO) expression increased in irradiated dermal fibroblasts and skin tissue, and SASP and cell senescence were regulated by 5-LO through p38 phosphorylation. Finally, the inhibition of 5-LO following treatment with zileuton inhibited SASP and mitigated radiation ulcers in animal models. Our results demonstrate that inhibition of SASP from senescent cells by zileuton can effectively mitigate radiation-induced cutaneous ulcers, indicating that inhibition of 5-LO might be a viable strategy for patients with this condition.

Metformin Protects the Intestinal Barrier by Activating Goblet Cell Maturation and Epithelial Proliferation in Radiation-Induced Enteropathy.

Radiotherapy or accidental exposure to high-dose radiation can cause severe damage to healthy organs. The gastrointestinal (GI) tract is a radiation-sensitive organ of the body. The intestinal barrier is the first line of defense in the GI tract, and consists of mucus secreted by goblet cells and a monolayer of epithelium. Intestinal stem cells (ISCs) help in barrier maintenance and intestinal function after injury by regulating efficient regeneration of the epithelium. The Wnt/ß-catenin pathway plays a critical role in maintaining the intestinal epithelium and regulates ISC self-renewal. Metformin is the most widely used antidiabetic drug in clinical practice, and its anti-inflammatory, antioxidative, and antiapoptotic effects have also been widely studied. In this study, we investigated whether metformin alleviated radiation-induced enteropathy by focusing on its role in protecting the epithelial barrier. We found that metformin alleviated radiation-induced enteropathy, with increased villi length and crypt numbers, and restored the intestinal barrier function in the irradiated intestine. In a radiation-induced enteropathy mouse model, metformin treatment increased tight-junction expression in the epithelium and inhibited bacterial translocation to mesenteric lymph nodes. Metformin increased the number of ISCs from radiation toxicity and enhanced epithelial repair by activating Wnt/ß-catenin signaling. These data suggested that metformin may be a potential therapeutic agent for radiation-induced enteropathy.

Bias-corrected Hp(10)-to-Organ-Absorbed Dose Conversion Coefficients for the Epidemiological Study of Korean Radiation Workers.

Background: The effects of radiation on the health of radiation workers who are constantly susceptible to occupational exposure must be assessed based on an accurate and reliable reconstruction of organ-absorbed doses that can be calculated using personal dosimeter readings measured as Hp(10) and dose conversion coefficients. However, the data used in dose reconstruction contain significant biases arising from a lack of reality and could result in an inaccurate measure of organ-absorbed doses. Therefore, this study quantified the biases involved in organ dose reconstruction and calculated the bias-corrected Hp(10)-to-organ-absorbed dose coefficients for the use in epidemiological studies of Korean radiation workers. Materials and Methods: Two major biases were considered: (1) the bias in Hp(10) arising from the difference between the dosimeter calibration geometry and the actual exposure geometry and (2) the bias in air kerma-to-Hp(10) conversion coefficients resulting from geometric differences between the human body and slab phantom. The biases were quantified by implementing personal dosimeters on the slab and human phantoms coupled with Monte Carlo method and considered to calculate the bias-corrected Hp(10)-to-organ-absorbed dose conversion coefficients. Results and Discussion: The bias in Hp(10) was significant for large incident angles and low energies (e.g., 0.32 for right lateral at 218 keV), whereas the bias in dose coefficients was significant for the posterior-anterior (PA) geometry only (e.g., 0.79 at 218 keV). The bias-corrected Hp(10)-to-organ-absorbed dose conversion coefficients derived in this study were up to 3.09-fold greater than those from ICRP publications without considering the biases. Conclusion: The obtained results will aid future studies in assessing the health effects of occupational exposure of Korean radiation workers. The bias-corrected dose coefficients of this study can be used to calculate organ doses for Korean radiation workers based personal dose records.

PINX1 promotes malignant transformation of thyroid cancer through the activation of the AKT/MAPK/ß-catenin signaling pathway.

Although thyroid cancer is the most prevalent endocrine malignancy, overall patients with thyroid cancer have a good long-term survival. However, a small percentage of patients with progressive thyroid cancer have poor outcomes, and the genetic drivers playing a key role thyroid cancer progression are mostly unknown. Here, we investigated the role of the PINX1 in thyroid cancer progression. Interestingly, PINX1 expression was significantly higher in ATC than in PTC in both patients and cell lines. When PINX1 was knockdown in ATC cells, cell proliferation rates, colony formation capacity, and cell cycle progression were significantly reduced. Furthermore, cell motility and the expression of EMT drivers were reduced by PINX1 downregulation. In contrast, the overexpression of PINX1 in PTC cells significantly increased those phenotypes of tumor progression, which demonstrates that PINX1 could promote tumor proliferation and malignant transformation in both PTC and ATC cells. To further understand whether PINX1 is also involved in the progression of PTC to ATC, we examined PI3K/AKT, MAPK, and ß-catenin signaling activation after PINX1 modulation. Decreased PINX1 expression reduced the levels of p-AKT, p-ERK, p-p38, and ß-catenin in ATC cells, but the increase of PINX1 expression upregulated the phosphorylation of AKT, ERK, and p38 and the levels of ß-catenin in PTC cells. These results were all confirmed in xenograft mouse tumors. Our findings suggest that PINX1 regulates thyroid cancer progression by promoting cell proliferation, EMT, and signaling activation, and support the hypothesis that PINX1 could be a prognostic marker and a therapeutic target of thyroid cancer.

Reliability and Validity of a Nationwide Survey (the Korean Radiation Workers Study).

BACKGROUND: This study aimed to evaluate the reliability and validity of the self-administered questionnaire for Korean radiation workers. METHODS: From May 24, 2016, to June 30, 2017, 20,608 participants completed the questionnaire, providing information on sociodemographics, lifestyle, work history and practices, medical radiation exposure, and medical history, which was linked to the National Dose Registry and the National Cancer Registry. The validity of the questionnaire was evaluated using the responses of 20,608 workers, and reliability was evaluated using the responses of 3043 workers who responded to the survey twice. RESULTS: Responses concerning demographic characteristics and lifestyle showed reliability with a moderate-to-high agreement (kappa: 0.43-0.99), whereas responses concerning occupation and medical radiation exposure had a wide range of agreement (kappa: 0.05-0.95), possibly owing to temporal variability during employment. Regarding validity, responses to the question about the first year of employment had an excellent agreement with the national registry (intraclass correlation coefficient = 0.9); however, responses on cancer history had a wide range of agreement (kappa: 0.22-0.85). CONCLUSION: Although the reliability and validity of the questionnaire were not distinguished by demographic characteristics, they tended to be low among participants whose occupational radiation exposure was minimal. Overall, the information collected can be reliable for epidemiological studies; however, caution must be exercised when using information such as medical exposure and work practices, which are prone to temporal variability.

Chromosome aberration dynamics in breast cancer patients treated with radiotherapy: Implications for radiation biodosimetry.

Although radiological accidents often result in partial-body radiation exposure, most biodosimetry studies focus on estimating whole-body exposure doses. We have evaluated time-dependent changes in chromosomal aberrations before, during, and after localized fractionated radiotherapy. Twelve patients with carcinoma in situ of the breast who underwent identical adjuvant radiation therapy (50 Gy in 25 fractions) were included in the study. Lymphocytes were collected from patients before, during, and after radiotherapy, to measure chromosome aberrations, such as dicentric chromosomes and translocations. Chromosome aberrations were then used to calculate whole- and partial-body biological absorbed doses of radiation. Dicentric chromosome frequencies in all study participants increased during radiotherapy (p < 0.05 in Kruskal-Wallis test). Increases of translocation frequencies during radiotherapy were observed in seven of the twelve patients. The increased levels of dicentric chromosomes and translocations persisted throughout our 1-year follow-up, and evidence of partial-body exposure (such as Papworth's U-value > 1.96) was observed more than 1 year after radiotherapy. We found that cytogenetic biomarkers reflected partial-body fractionated radiation exposure more than 1 year post-exposure. Our findings suggest that chromosome aberrations can be used to estimate biological absorbed radiation doses and can inform medical intervention for individuals suspected of fractionated or partial-body radiation exposure.

Non-cancer disease prevalence and association with occupational radiation exposure among Korean radiation workers.

Radiation-induced cancer risks have known stochastic effects; however, regarding non-cancer diseases, evidence of risk at low radiation doses remains unclear. We aimed to identify underlying characteristics concerning non-cancer disease prevalence and determine associations with radiation dose among Korean radiation workers. Using a nationwide baseline survey, 20,608 workers were enrolled. Data concerning participant demographics, occupational characteristics, lifestyle, and lifetime prevalence of non-cancer diseases were linked to a national dose registry. We compared non-cancer disease prevalences in the Korean general population with those in this cohort and undertook a dose-response analysis concerning the cumulative dose. Hyperlipidemia (10.6%), circulatory (9.6%), and respiratory (4.1%) system diseases, followed by thyroid diseases (3.5%), had the highest prevalences, with hyperlipidemia, thyroid diseases, and hepatitis prevalence being higher in the cohort than in the general population. Radiation doses were associated with elevated prevalences of most diseases; however, associations were attenuated and not significant after adjusting for confounders, except for musculoskeletal system diseases (prevalence odds ratio [POR]/10 mSv, 1.03; 95% confidence interval [CI] 1.00-1.07) and cataracts (POR/10 mSv, 1.04; 95% CI 1.00-1.07). Further studies are warranted to investigate the causality of those non-cancer diseases involving more varied confounders such as physical and psychosocial stresses and ultraviolet light.

Metallothionein 2 activation by pravastatin reinforces epithelial integrity and ameliorates radiation-induced enteropathy.

BACKGROUND: Radiotherapy or accidental exposure to ionizing radiation causes severe damage of healthy intestinal tissues. Intestinal barrier function is highly sensitive to ionizing radiation, and loss of epithelial integrity results in mucosal inflammation, bacterial translocation, and endotoxemia. Few studies have of epithelial integrity as a therapeutic target to treat radiation toxicity. Here, we examined the effects of pravastatin (PS) and the molecular mechanisms underlying epithelial integrity on radiation-induced enteropathy. METHODS: The radio-mitigative effects of PS were evaluated in a minipig model by quantifying clinical symptoms, and performing histological and serological analyses and mRNA sequencing in intestinal tissues. To evaluate the role of intercellular junctions on radiation damage, we used tight junction regulator and metallothionein 2 (MT2) as treatments in a mouse model of radiation-induced enteropathy. Caco-2 monolayers were used to examine functional epithelial integrityand intercellular junction expression. FINDING: Using a minipig model of pharmaceutical oral bioavailability, we found that PS mitigated acute radiation-induced enteropathy. PS-treated irradiated minipigs had mild clinical symptoms, lower intestinal inflammation and endotoxin levels, and improved gastrointestinal integrity, compared with control group animals. The results of mRNA sequencing analysis indicated that PS treatment markedly influenced intercellular junctions by inhibiting p38 MAPK signaling in the irradiated intestinal epithelium. The PS-regulated gene MT2 improved the epithelial barrier via enhancement of intercellular junctions in radiation-induced enteropathy. INTERPRETATION: PS regulated epithelial integrity by modulating MT2 in radiation-damaged epithelial cells. These findings suggested that maintenance of epithelial integrity is a novel therapeutic target for treatment of radiation-induced gastrointestinal damage. FUNDING: As stated in the Acknowledgments.