Meibomian glands (MGs) are holocrine glands that secrete lipids to maintain the homeostasis of ocular surface, and their dysfunction leads to dry eye disease. Herein, we established long-term 3D organoid culture for murine and human MGs, which retained the cell lineages and lipid-producing ability. The organoids mimicked the drug treatment responses and generated functional MGs after orthotopic transplantation. Inspired by organoid cultures, we found FGF10 eye drops could rescue all-trans retinoic acid-induced MG dysfunction in mice. Besides, nicotinamide uniquely hampered the human MG organoid expansion by inhibiting FGF10 signaling. Single-cell atlas and lipidome not only aligned the delineated cell types and featured lipids between human MGs and organoids, but highlighting MAPK signaling inhibition enhanced acinar cell differentiation and functional maturation of MG organoids. In summary, this study established an organoid platform to explore epithelial homeostasis and dysfunction of MGs, facilitating drug development and regenerative medicine for dry eye disease.
{"title":"Human meibomian gland organoids to study epithelial homeostasis and dysfunction.","authors":"Chuyue Yu, Xichen Wan, Jinsong Wei, Zhaoting Xu, Xingru Wu, Xiaoye Wang, Yabo Mi, Yiming Zhang, Dan Wu, Xujiao Zhou, Qihua Le, Jianjiang Xu, Chen Zhao, Xinghuai Sun, Xingtao Zhou, Jiaxu Hong, Bing Zhao","doi":"10.1093/procel/pwaf095","DOIUrl":"https://doi.org/10.1093/procel/pwaf095","url":null,"abstract":"<p><p>Meibomian glands (MGs) are holocrine glands that secrete lipids to maintain the homeostasis of ocular surface, and their dysfunction leads to dry eye disease. Herein, we established long-term 3D organoid culture for murine and human MGs, which retained the cell lineages and lipid-producing ability. The organoids mimicked the drug treatment responses and generated functional MGs after orthotopic transplantation. Inspired by organoid cultures, we found FGF10 eye drops could rescue all-trans retinoic acid-induced MG dysfunction in mice. Besides, nicotinamide uniquely hampered the human MG organoid expansion by inhibiting FGF10 signaling. Single-cell atlas and lipidome not only aligned the delineated cell types and featured lipids between human MGs and organoids, but highlighting MAPK signaling inhibition enhanced acinar cell differentiation and functional maturation of MG organoids. In summary, this study established an organoid platform to explore epithelial homeostasis and dysfunction of MGs, facilitating drug development and regenerative medicine for dry eye disease.</p>","PeriodicalId":20790,"journal":{"name":"Protein & Cell","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145482966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gustav van Niekerk,Yana Kumpanenko,Joran Degryse,Johan Fevery,Kai Dallmeier
Postprandially reabsorbed bile acids, along with various peptide hormones released following a meal, orchestrate complex events associated with digestion and prepare the body for the disposal of incoming nutrients by regulating metabolism. Interestingly, these factors have also been shown to modulate immune function. For example, recent interest in weight-loss agents such as semaglutide has demonstrated their ability to attenuate inflammation and provide benefits in diverse clinical contexts characterized by inflammatory responses. This raises an important question: why do hormones with well-established roles in digestion and metabolism also influence immunity? Here, we propose that the immune-regulatory activity of peptide hormones, together with postprandially reabsorbed bile acids, contributes to another remarkable phenomenon: the exceptional immune tolerance of the liver. While it is well established that the liver is an immunologically tolerant organ, the precise mechanisms underlying this skewed immunological tone remain poorly understood. Hepatic immune tolerance has generally been considered an intrinsic property of the liver, arising from autonomous mechanisms. Here, we highlight that various entero-pancreatic endocrine factors delivered to the liver via the portal vein activate cAMP signalling, thereby promoting immune tolerance and attenuating inflammatory tone within the liver. Critically, because these endocrine factors reach the liver at elevated concentrations through the portal vein before dilution in the systemic circulation, they profoundly shape the hepatic immune environment. Physiologically, this system ensures that the liver tolerates diet- and gut-derived inflammogens. Finally, we discuss several implications of this mechanism.
{"title":"Peptide Hormones and Bile Acids Shaping Immune Tolerance of the Liver: Implications and Applications.","authors":"Gustav van Niekerk,Yana Kumpanenko,Joran Degryse,Johan Fevery,Kai Dallmeier","doi":"10.1093/procel/pwaf096","DOIUrl":"https://doi.org/10.1093/procel/pwaf096","url":null,"abstract":"Postprandially reabsorbed bile acids, along with various peptide hormones released following a meal, orchestrate complex events associated with digestion and prepare the body for the disposal of incoming nutrients by regulating metabolism. Interestingly, these factors have also been shown to modulate immune function. For example, recent interest in weight-loss agents such as semaglutide has demonstrated their ability to attenuate inflammation and provide benefits in diverse clinical contexts characterized by inflammatory responses. This raises an important question: why do hormones with well-established roles in digestion and metabolism also influence immunity? Here, we propose that the immune-regulatory activity of peptide hormones, together with postprandially reabsorbed bile acids, contributes to another remarkable phenomenon: the exceptional immune tolerance of the liver. While it is well established that the liver is an immunologically tolerant organ, the precise mechanisms underlying this skewed immunological tone remain poorly understood. Hepatic immune tolerance has generally been considered an intrinsic property of the liver, arising from autonomous mechanisms. Here, we highlight that various entero-pancreatic endocrine factors delivered to the liver via the portal vein activate cAMP signalling, thereby promoting immune tolerance and attenuating inflammatory tone within the liver. Critically, because these endocrine factors reach the liver at elevated concentrations through the portal vein before dilution in the systemic circulation, they profoundly shape the hepatic immune environment. Physiologically, this system ensures that the liver tolerates diet- and gut-derived inflammogens. Finally, we discuss several implications of this mechanism.","PeriodicalId":20790,"journal":{"name":"Protein & Cell","volume":"1 1","pages":""},"PeriodicalIF":21.1,"publicationDate":"2025-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145477549","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
DNA-histone cross-links (DHCs) frequently arise within nucleosomes during DNA damage and repair processes. However, the functional consequences of DHC within nucleosomes remain largely unexplored. In this study, we prepared structurally homogeneous nucleosomes containing a single, site-specific DHC using click chemistry and systematically evaluated the impact of DHC on nucleosome structure and function. Our results show that DHC markedly enhances nucleosome thermal stability and completely blocks both thermally induced passive sliding and chromatin remodeler-mediated active sliding. Moreover, DHC obstructs SP6 RNA polymerase-driven transcription elongation through nucleosomes, leading to premature termination approximately 15 bp upstream of the cross-linking site. DHC also increases histone resistance to proteolytic digestion within nucleosomes. These findings suggest that even a single DHC can substantially lock and rigidify the nucleosome structure and broadly interfere with the recognition and processing of nucleosomes by various cellular machineries, thereby rendering DHC a highly toxic and persistent form of DNA damage. This in vitro study highlights the unique impact of DHC on nucleosome architecture and is expected to motivate further exploration of its biological roles in vivo.
{"title":"DNA - histone cross-link locks the nucleosome structure and disrupts its recognition and processing.","authors":"Xiajing Shan,Gaoyuan Ji,Jiahui Li,Mengtian Ren,Jingke Ma,Yifei Zhou,Haitao Li,Chuanzheng Zhou","doi":"10.1093/procel/pwaf094","DOIUrl":"https://doi.org/10.1093/procel/pwaf094","url":null,"abstract":"DNA-histone cross-links (DHCs) frequently arise within nucleosomes during DNA damage and repair processes. However, the functional consequences of DHC within nucleosomes remain largely unexplored. In this study, we prepared structurally homogeneous nucleosomes containing a single, site-specific DHC using click chemistry and systematically evaluated the impact of DHC on nucleosome structure and function. Our results show that DHC markedly enhances nucleosome thermal stability and completely blocks both thermally induced passive sliding and chromatin remodeler-mediated active sliding. Moreover, DHC obstructs SP6 RNA polymerase-driven transcription elongation through nucleosomes, leading to premature termination approximately 15 bp upstream of the cross-linking site. DHC also increases histone resistance to proteolytic digestion within nucleosomes. These findings suggest that even a single DHC can substantially lock and rigidify the nucleosome structure and broadly interfere with the recognition and processing of nucleosomes by various cellular machineries, thereby rendering DHC a highly toxic and persistent form of DNA damage. This in vitro study highlights the unique impact of DHC on nucleosome architecture and is expected to motivate further exploration of its biological roles in vivo.","PeriodicalId":20790,"journal":{"name":"Protein & Cell","volume":"169 1","pages":""},"PeriodicalIF":21.1,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145472809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The liver is a common site for cancer metastasis and a key metabolic organ. Lipid metabolism irregularities are linked to liver metastasis risk, but the mechanisms are not fully understood. Herein, in colorectal liver metastases (CRLM) clinical samples, lipid metabolism was broadly dysregulated, and lipid metabolites accumulated, as shown by integrated transcriptome and lipidomics analyses. Functionally, lipids deposition promotes liver metastasis in vitro and in vivo. Mechanistically, lipid deposition significantly enhances YTHDF3-mediated m6A modification and degradation of PPARα, which is crucial for liver metastasis. This process reduces the β-hydroxybutyrylation of YTHDF3, thereby promoting LLPS and increasing the stability of YTHDF3, which in turn facilitates the progression of CRC and liver metastasis. Furthermore, lipid deposition induces the interaction between STAT3 and YAP, activating YTHDF3 transcription. These two regulatory mechanisms synergize to drive YTHDF3 accumulation in lipid-rich metastatic lesions. In summary, our findings reveal that lipid deposition promotes LLPS-mediated m6A modification and decreases β-hydroxybutyrylation in liver metastasis, offering new strategies for the treatment of CRLM.
{"title":"Lipid deposition promotes YTHDF3-mediated m6A modification of PPARα to facilitate liver metastasis of colorectal cancer.","authors":"Wen Ni,Yuanyuan Xu,Mengrou Zhang,Li Yuqing,Piao Huang,Zhun Li,Qi Wu,Hui Mo,Yibiao Ye,Yuhui Li,Aijun Zhou,Su Yao,Shilin Zhi,Jiali Qi,Shuhui Yu,Saiqi He,Jianming Li","doi":"10.1093/procel/pwaf092","DOIUrl":"https://doi.org/10.1093/procel/pwaf092","url":null,"abstract":"The liver is a common site for cancer metastasis and a key metabolic organ. Lipid metabolism irregularities are linked to liver metastasis risk, but the mechanisms are not fully understood. Herein, in colorectal liver metastases (CRLM) clinical samples, lipid metabolism was broadly dysregulated, and lipid metabolites accumulated, as shown by integrated transcriptome and lipidomics analyses. Functionally, lipids deposition promotes liver metastasis in vitro and in vivo. Mechanistically, lipid deposition significantly enhances YTHDF3-mediated m6A modification and degradation of PPARα, which is crucial for liver metastasis. This process reduces the β-hydroxybutyrylation of YTHDF3, thereby promoting LLPS and increasing the stability of YTHDF3, which in turn facilitates the progression of CRC and liver metastasis. Furthermore, lipid deposition induces the interaction between STAT3 and YAP, activating YTHDF3 transcription. These two regulatory mechanisms synergize to drive YTHDF3 accumulation in lipid-rich metastatic lesions. In summary, our findings reveal that lipid deposition promotes LLPS-mediated m6A modification and decreases β-hydroxybutyrylation in liver metastasis, offering new strategies for the treatment of CRLM.","PeriodicalId":20790,"journal":{"name":"Protein & Cell","volume":"13 1","pages":""},"PeriodicalIF":21.1,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145472810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Liu Chaohua, Xu Fei, Wu Yutuan, Li Jiana, Ni Mengdong, Xia Siyu, Chen Lihua, Zhao Haiyun, Yu Min, Zhou Yuqi, Zhang Meiqin, Li Jiajia, Wu Xiaohua, Huang Yan, Zhu Tao, Chen Xiaojun
Epithelial ovarian cancer (EOC) is an aggressive malignancy with limited therapeutic options. Poly(ADP-ribose) polymerase inhibitors (PARPi) have shown remarkable efficacy, especially in BRCA-mutant patients, and are approved as maintenance therapy to prevent recurrence after initial response to chemotherapy. However, the development of PARPi resistance poses a major clinical challenge. This study utilized a whole-genome CRISPR-Cas9 genetic screening to identify genes associated with PARPi sensitivity upon knockout. Based on the screening and validated through further experiments, we confirmed that CLK1 knockdown is synthetically lethal with PARPi in ovarian cancer. The combination of the PARPi Olaparib and CLK1 inhibitor TG003 exhibited potent anti-proliferative effects both in vitro and in vivo. Mechanistically, CLK1 inhibition downregulated the functional ERCC1-202 isoform, resulting in enhanced DNA damage and apoptosis. Our findings reveal a novel mechanism underlying PARPi sensitivity and suggest that targeting CLK1 in combination with PARPi may represent a promising therapeutic strategy for PARPi-resistant ovarian cancer.
{"title":"Genome-wide CRISPR-Cas9 screening identifies CLK1 inhibition as a strategy to restore PARP inhibitor sensitivity via ERCC1 isoform switching.","authors":"Liu Chaohua, Xu Fei, Wu Yutuan, Li Jiana, Ni Mengdong, Xia Siyu, Chen Lihua, Zhao Haiyun, Yu Min, Zhou Yuqi, Zhang Meiqin, Li Jiajia, Wu Xiaohua, Huang Yan, Zhu Tao, Chen Xiaojun","doi":"10.1093/procel/pwaf091","DOIUrl":"https://doi.org/10.1093/procel/pwaf091","url":null,"abstract":"<p><p>Epithelial ovarian cancer (EOC) is an aggressive malignancy with limited therapeutic options. Poly(ADP-ribose) polymerase inhibitors (PARPi) have shown remarkable efficacy, especially in BRCA-mutant patients, and are approved as maintenance therapy to prevent recurrence after initial response to chemotherapy. However, the development of PARPi resistance poses a major clinical challenge. This study utilized a whole-genome CRISPR-Cas9 genetic screening to identify genes associated with PARPi sensitivity upon knockout. Based on the screening and validated through further experiments, we confirmed that CLK1 knockdown is synthetically lethal with PARPi in ovarian cancer. The combination of the PARPi Olaparib and CLK1 inhibitor TG003 exhibited potent anti-proliferative effects both in vitro and in vivo. Mechanistically, CLK1 inhibition downregulated the functional ERCC1-202 isoform, resulting in enhanced DNA damage and apoptosis. Our findings reveal a novel mechanism underlying PARPi sensitivity and suggest that targeting CLK1 in combination with PARPi may represent a promising therapeutic strategy for PARPi-resistant ovarian cancer.</p>","PeriodicalId":20790,"journal":{"name":"Protein & Cell","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145452798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Inheritance and advancement in biochemistry: the pioneering research of Szu-Chih Liu.","authors":"Quanxiu Li, Cheng Zhen","doi":"10.1093/procel/pwaf030","DOIUrl":"10.1093/procel/pwaf030","url":null,"abstract":"","PeriodicalId":20790,"journal":{"name":"Protein & Cell","volume":"16 11","pages":"919-927"},"PeriodicalIF":12.8,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12698186/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145744345","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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