91猫先生

工作经歷

2026. 08 – present    副教授/ 长庚大学/ 临床医学研究所.

2026. 01 – lifetime    EMBO outstanding early-career group leaders.

2022. 01 – 2025. 12   EMBO Global Investigator.

2021. 02 – 2026. 07   副教授/ 台北医学大学/ 医学系/ 生理科.

2016. 12 – 2021. 01   助理教授/ 台北医学大学/ 医学系/ 生理科.

研究室

研究方向及特色

本实验室的研究核心建构於「时间肝臟病学（Chronohepatology）」与「细胞基因组含量转换（Genome content Transition）」的交叉领域。本团队致力於解开一个核心科学谜题：当人体最重要的代谢与生物鐘器官肝臟，面临昼夜节律（Circadian clock）失调以及外界环境压力衝击时，如何透过调控细胞多倍体化（Polyploidization）以及多倍体逆转（Polyploidy Reversal）的分子开关，让细胞能在生理与病理状态下进行动态的调控。根据团队发表的系列研究，研究可系统性拆解為以下叁大方向, 来解码生物鐘节律、基因组转换、与癌前病变的叁角网络：

1. 昼夜节律对肝臟多倍体化的分子调控机制

在正常生理状态下，哺乳动物的肝臟具备独特且普遍的「多倍体（Polyploidy）」现象（即细胞核内含有两套以上的染色体组）。本团队在第一篇论文（Nature Communications, 2017）中，首次将生物鐘与这项细胞特徵串联，发现昼夜节律是控制肝细胞多倍体化发育进程的关键时鐘。研究证实，当核心时鐘基因Periods发生突变或因环境压力引发生物鐘紊乱时，会直接干扰下游 Mkp1-Erk1/2 讯号通路的24小时动态振盪。此通路的节律性失调，会导致肝细胞在进行有丝分裂时出现胞质分裂失败（Cytokinesis failure），进而迫使原本正常的二倍体或低倍体肝细胞，异常加速转化為超高倍体细胞(hyperpolyploid cell)。

2. 肝细胞「超多倍体化」作為肝癌前病变的啟动因子

过去学术界普遍认為多倍体化是肝臟老化或应对代谢压力的保护性机制。然而，本团队在第二篇论文（Nature Communications, 2021）中提出了颠覆性的转译医学观点：过度的肝细胞多倍体化（Hyperpolyploidization）本质上是肝癌前病变（Preneoplastic lesion）的开端。团队在动物模型中实证，当肝细胞因慢性发炎或节律紊乱被推向超高倍体时，过多的基因组会使细胞面临极高的染色体分离不稳定性（Chromosomal Instability）。后续透过多倍体逆转的步骤重新退回低倍体细胞的过程时会导致基因组重新「洗牌」而直接促使细胞发生恶性转型，造成肝癌前期病灶的形成。

3. 全核消除（Whole-nucleus elimination）调控多倍体逆转防线，阻断癌细胞生成

本实验室发现, 老鼠暴露在 genotoxin的环境压力下, 会改变肝细胞的细胞核数目状态, 這種狀態是透過 移除 特定細胞核所造成的一個特殊全核消除結果。我們發現, 全核消除可以被视為细胞面对毁灭性 DNA 损伤时的自救与防御机制。它将高度突变、可能发生恶性转型的细胞核核物质直接「打包消除」，防止这些带有致癌突变的遗传物质进入下一次有丝分裂，从而维持了全肝组织的基因组稳定性。它本质上是一种超大型的选择性核自噬机制（Macro-nucleophagy），在抑癌与抗癌领域扮演着「基因组终极清道夫」的关键防御角色。

4. 「时间药理学（Chronopharmacology）」与标靶精準医疗之实践

本实验室与西北农林大学的陈华涛教授合作, 共同开发「CircaVal」大数据/多体学昼夜节律分析平台。该平台能针对高通量定序（如 RNA-seq、Nascent-seq 新生转录组、Ribo-seq 转译组）数据进行精準的节律演算法（Rhythmicity Score Explorer）计算，对接长庚肝病临床巨量资料库（CGRD）与病患组织检体，建构出全台首创的「后B肝时间标靶医疗精準预测平台」。能在海量临床数据中直接解读具备 24 小时动态波动的时间靶点。开发「时间定向给药策略（Chronotherapy）」，评估抗癌标靶药物、发炎抑制剂在一天之中哪一个「时间窗口」给予，最能顺应肝臟时鐘基因的节律，进而在极大化毒杀癌前病变细胞的同时，利用时间差完美避开对正常肝细胞线粒体造成的毒性。将临床大数据与基础分子生物学实验无缝对接。

总结

本研究室是一个高度聚焦於「时间（Time）」与「倍性（Ploidy）」双重维度的前沿转译医学实验室。我们的研究不仅重新定义了昼夜节律失调引发肝癌的演化路径，更透过建立多倍体逆转与时间药理学平台，為未来临床上慢性肝病与肝癌前期病变的「精準时间医疗」提供了新思维的解决方案。

参考资料

1. C.-S. Wu?, W.-H. Lu?, M.-C. Hung*, Y.-S. Huang*, and H.-W. Chao?*. From polyploidization to polyploidy reversal, the role in normal and disease states. Trends in Genetics. 2022 Oct 38(10):991-995. (? Equal contribution), (* Corresponding) (IF=12.9; Field order: 4/191)

2. H. Lin?, Y.-S. Huang?, J.-M. Fustin, M. Doi, H. Chen, H.-H. Lai, S.-H. Lin, Y.-L. Lee, P.-C. King, H.-S. Hou, H.-W. Chen, P.-Y. Young, and H.-W. Chao?*, Hyperpolyploidization of hepatocyte initiates preneoplastic lesion formation in the liver. Nature Communications, 2021 Jan 28; 12(1):645. (? Equal contribution) (*, Corresponding) (IF=18.1; Field order: 4/191)

3. H.-W. Chao, M. Doi, J.-M. Fustin, H. Chen, Y. Maeda, H. Hayashi, R. Tanaka, M. Sugawa, N. Mizukuchi, Y. Yamaguchi, J. Yasunaga, M. Matsuoka, M. Sakai, M. Matsumoto, S. Hamada, H Okamura*, Circadian Clock Regulates Hepatic Polyploidy by Modulating Mkp1-ERk1/2 Signalling Pathway. Nature Communications, 2017 Dec 21; 8(1):2238. (IF=18.1; Field order: 4/191)

近期发表论文

1. W.-B. Lu, Y.-S. Huang, J.-C. Wu, L.-W. Chen, I-W. Lin, P.-C. Chen, P.-H. Chen, C.-Y. Huang, T.-T. Tai, S.-H. Huang, S.-H. Wu, F.-S. Wang, H.-W. Chao *, M.-H. Tai *. Irisin Gene Delivery Elicits Sustained Amelioration of Diabetes in Akita Mice via Insulin-Independent Regulation of Hepatic Glucose Metabolism. 2026 Aug., Diabetes. Accepted (* Corresponding) (IF=9.3; Field order: 13/198)

# This study identifies an insulin-independent pathway of the liver to ameliorate diabetes symptoms through upregulation of Irisin in the hepatocytes in Akita-diabetic mice.

2. W. Yang, X. Wang, B. Xiao, C. Li, Y. Guo, K. Tang, A. Wang, H.-W. Chao*, Y. Jin*, H. Chen*. Berberine alleviates LPS-induced inflammatory response by targeted activation of NR1D1 in bovine endometrial epithelial cells. International Immunopharmacology, 2026 Aug. 15, (13) 116858. (* Corresponding) (IF=5.6; Field order: 48/356)

3. G. Han, X. Wu, X. Xiao, T. Guo, D. Li, H. Zhang, D. Gao, C. Li, A. Wang, H.-W. Chao*, Y. Jin*, H. Chen*. RhythmInsight: An Interactive Web Platform for Circadian and Diurnal Rhythmic Analysis and Visualization. Journal of Biological Rhythms, 2026 May 05, 07487304261437377. (* Corresponding) (IF=3.0; Field order: 26/106)  

4. H.-W. Chao, Y.-M.-J. Lin, C.-S. Wu, Biomarker-Based Precision Prediction of Immunotherapy Response in Hepatocellular Carcinoma. Diagnostics, 2025 Dec. 28, 16 (1), 85 (IF=3.6; Field order: 61/336)

5. C.-S. Wu, T.-Y. Lee, H.-W. Chao*. Targeting glypican-3 as a new frontier in liver cancer therapy. World journal of hepatology, 2025 Sep. 27, 7 (9), 107671 (* Corresponding) (IF=3.4; Field order: 55/153)

6. G. Han, D. Li, H. Zhang, C. Li, L. Yang, T. Ma, X. Wang, B. Ma, X. Wu, Y. Tao, Z. Wang, A. Wang, H.-W. Chao*, Y. Jin* & H. Chen*. A transcriptomic Dataset of Liver tissues from Global and Liver Specific Bmal1 Knockout Mice. Scientific Data. 2025 Feb. 13;18 (6):4822-4839. (* Corresponding) (IF=7.2; Field order: 17/140)

# This study highlights the critical role of BMAL1 in the liver function by transcriptomic data from global and liver-specific Bmal1 knockout mice.

7. Y.-W. Chao?, Y.-L. Lee?, C.-S. Tseng?, L. Wang, K.-C. Hsia, H. Chen, J.-M. Fustin, S. Azeem, T.-T. Chang, Y.-P. Hsueh*, Y.-S. Huang*, H.-W. Chao?*. Improved CaP nanoparticles transforming nucleic acid and protein delivery to neural primary culture and stem cells. ACS NANO. 2024 Feb. 13;18 (6):4822-4839. (? Equal contribution) (* Corresponding) (IF=17.2; Field order: 24/439)

# The first report provides the highly cost-effective non-viral system for delivery of nucleic acid and protein into primary cells.

8. W. Yang; M. Jin; Y. Wang; H. Zhao; X. Wang; Y. Guo; C. Li; B. Xiao; H. Zhang; K. Fouzia; A. Wang; H.-W. Chao*, Y. Jin*, H. Chen*. NR1D1 activation alleviates inflammatory response through inhibition of IL-6 expression in bovine endometrial epithelial cells. International Journal of Biological Macromolecules. 2024 Nov. 283, 137642 (* Corresponding) (IF=8.7; Field order: 5/95)

# The first report provides the evidence that activating the circadian clock receptor NR1D1 alleviates bovine endometritis.

9. H. Zhao, G. Han, Z. Jiang, D. Gao, H. Zhang, L. Yang, T. Ma, L. Gao, A. Wang, Q. Li, H.-W. Chao＊, Y. Jin＊, H. Chen＊. Identification of BMAL1-Regulated circadian genes in mouse liver and their potential association with hepatocellular carcinoma: Gys2 and Upp2 as promising candidates. Biochemical and Biophysical Research Comms. 2024 Feb. (696), 149422. (* Corresponding) (IF=2.5; Field order: 45/81)

10. C.-S. Wu?, W.-H. Lu?, M.-C. Hung*, Y.-S. Huang*, and H.-W. Chao?*. From polyploidization to polyploidy reversal, the role in normal and disease states. Trends in Genetics. 2022 Oct 38(10):991-995. (? Equal contribution), (* Corresponding) (IF=12.9; Field order: 4/191)

# The invited forum article to discuss the issue of genome content switch in organisms.

11. C.-W. Lin, D. Septyaningtrias?, H.-W. Chao?, M. Kond, K. Atarashi, K. Takeshita, K. Tamada, J. Nomura, Y. Sasagawa, K. Tanaka, I. Nikaido, K. Honda, T. J. McHugh and T. Takumi, A common epigenetic mechanism across different cellular origins underlies systemic immune dysregulation in autism. Molecular Psychiatry, 2022 May 02, (? Equal contribution) (IF=10.4; Field order: 11/313)

12. H.-W. Chao?, W.-H. Lu?, P.-Y. Lin, S.-H. Lin, T.-H. Liu, and Y.-S. Huang. CPEB3-downregulated Nr3c1 mRNA translation confers resilience to developing posttraumatic stress disorder-like behavior in fear-conditioned mice. Neuropsychopharmacology, 2021 May 03, 46, p1669–1679 (? Equal contribution) (IF=7.6; Field order: 24/354)

# The first critical report demonstrates the role of RNA-binding protein in the formation of post-traumatic stress disorder.

13. Y. Xiao, L. Zhao, W. Li, X. Wang, T. Ma, L. Yang, L. Gao, C. Li, M. Zhang, D. Yang, J. Zhang, H. Jiang, H. Zhao, Y. Wang, H.-W. Chao, A. Wang, Y. Jin, H. Chen, Circadian clock gene BMAL1 controls testosterone production by regulating steroidogenesis-related gene transcription in goat Leydig cells. Journal of Cellular Physiology, 2021 Feb 17, 236 (9), p6706-6725 (IF=4.0; Field order: 23/85)

Assistant Professor Period (2016/12~2021/01)

14. H. Lin?, Y.-S. Huang?, J.-M. Fustin, M. Doi, H. Chen, H.-H. Lai, S.-H. Lin, Y.-L. Lee, P.-C. King, H.-S. Hou, H.-W. Chen, P.-Y. Young, and H.-W. Chao?*, Hyperpolyploidization of hepatocyte initiates preneoplastic lesion formation in the liver. Nature Communications, 2021 Jan 28; 12(1):645. (? Equal contribution) (*, Corresponding) (IF=18.1; Field order: 8/135)

# Featured in a Nature Communications Editors’ Highlights webpage “Cancer”.

# Commented by Nature Communications, entitled "Ploidy dynamics increase the risk of liver cancer initiation".

# Recommended by Faculty Opinions as Very Good article.

15. Y.-S. Huang, K.-C. Lu, H.-W. Chao, A. Chen, T.-K. Chao, C.-Y. Guo, H.-Y. Hsieh, H.-M. Shih, H.-K. Sytwu, C.-C. Wu, The MTNR1A mRNA is stabilized by the cytoplasmic hnRNPL in renal tubular cells. Journal of Cellular Physiology., 2020 July 30; 236 (3): p2023-2035 (IF=4.0; Field order: 23/85)

16. H.-W. Chao?, Y.-T. Lai?, A. C.-Y. Lai, S.-H. Lin, Y.-J. Chang, and Y.-S. Huang, CPEB2-activated PDGFRα mRNA translation is essential for myofibroblast proliferation and pulmonary alveologenesis., Journal of Biomedical Science, 2020 Apr 15; 27(1):52. (? Equal contribution) (IF=14.5; Field order: 8/191)

17. H.-W. Chao, M. Doi, J.-M. Fustin, H. Chen, Y. Maeda, H. Hayashi, R. Tanaka, M. Sugawa, N. Mizukuchi, Y. Yamaguchi, J. Yasunaga, M. Matsuoka, M. Sakai, M. Matsumoto, S. Hamada, H Okamura*, Circadian Clock Regulates Hepatic Polyploidy by Modulating Mkp1-ERk1/2 Signalling Pathway. Nature Communications, 2017 Dec 21; 8(1):2238. (IF=18.1; Field order: 8/135)

# The first critical report connects circadian clock to genome content switch and pathological polyploidy of the liver.

18. C.-S. Tseng, H.-W. Chao, H.-S. Huang and Y.-S. Huang, Olfactory Experience- and Developmental Stage-Dependent Control of CPEB4 Regulates c-Fos mRNA Translation for Granule Cell Survival. Cell Reports, 2017 Nov 21; 21(8):2264-2276. (IF=7.7; Field order: 36/205)