臨床醫學研究所

工作經歷

2026. 08 – present    副教授/ 長庚大學/ 臨床醫學研究所.

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

2022. 01 – 2025. 12   EMBO Global Investigator.

2021. 02 – 2026. 07   副教授/ 台北醫學大學/ 醫學系/ 生理科.

2016. 12 – 2021. 01   助理教授/ 台北醫學大學/ 醫學系/ 生理科.

研究室

研究方向及特色

本實驗室的研究核心建構於「時間肝臟病學（Chronohepatology）」與「細胞基因組含量轉換（Genome content Transition）」的交叉領域。本團隊致力於解開一個核心科學謎題：當人體最重要的代謝與生物鐘器官肝臟，面臨晝夜節律（Circadian clock）失調以及外界環境壓力衝擊時，如何透過調控細胞多倍體化（Polyploidization）以及多倍體逆轉（Polyploidy Reversal）的分子開關，讓細胞能在生理與病理狀態下進行動態的調控。根據團隊發表的系列研究，研究可系統性拆解為以下三大方向, 來解碼生物鐘節律、基因組轉換、與癌前病變的三角網絡：

1. 晝夜節律對肝臟多倍體化的分子調控機制

在正常生理狀態下，哺乳動物的肝臟具備獨特且普遍的「多倍體（Polyploidy）」現象（即細胞核內含有兩套以上的染色體組）。本團隊在第一篇論文（Nature Communications, 2017）中，首次將生物鐘與這項細胞特徵串聯，發現晝夜節律是控制肝細胞多倍體化發育進程的關鍵時鐘。研究證實，當核心時鐘基因Periods發生突變或因環境壓力引發生物鐘紊亂時，會直接干擾下游 Mkp1-Erk1/2 訊號通路的24小時動態振盪。此通路的節律性失調，會導致肝細胞在進行有絲分裂時出現胞質分裂失敗（Cytokinesis failure），進而迫使原本正常的二倍體或低倍體肝細胞，異常加速轉化為超高倍體細胞(hyperpolyploid cell)。

2. 肝細胞「超多倍體化」作為肝癌前病變的啟動因子

過去學術界普遍認為多倍體化是肝臟老化或應對代謝壓力的保護性機制。然而，本團隊在第二篇論文（Nature Communications, 2021）中提出了顛覆性的轉譯醫學觀點：過度的肝細胞多倍體化（Hyperpolyploidization）本質上是肝癌前病變（Preneoplastic lesion）的開端。團隊在動物模型中實證，當肝細胞因慢性發炎或節律紊亂被推向超高倍體時，過多的基因組會使細胞面臨極高的染色體分離不穩定性（Chromosomal Instability）。後續透過多倍體逆轉的步驟重新退回低倍體細胞的過程時會導致基因組重新「洗牌」而直接促使細胞發生惡性轉型，造成肝癌前期病灶的形成。

3. 全核消除（Whole-nucleus elimination）調控多倍體逆轉防線，阻斷癌細胞生成

本實驗室發現, 老鼠暴露在 genotoxin的環境壓力下, 會改變肝細胞的細胞核數目狀態, 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, 全核消除可以被視為細胞面對毀滅性 DNA 損傷時的自救與防禦機制。它將高度突變、可能發生惡性轉型的細胞核核物質直接「打包消除」，防止這些带有致癌突變的遺傳物質進入下一次有絲分裂，從而維持了全肝組織的基因組穩定性。它本質上是一種超大型的選擇性核自噬機制（Macro-nucleophagy），在抑癌與抗癌領域扮演著「基因組終極清道夫」的關鍵防禦角色。

4. 「時間藥理學（Chronopharmacology）」與標靶精準醫療之實踐

本實驗室與西北農林大學的陳華濤教授合作, 共同開發「CircaVal」大數據/多體學晝夜節律分析平台。該平台能針對高通量定序（如 RNA-seq、Nascent-seq 新生轉錄組、Ribo-seq 轉譯組）數據進行精準的節律演算法（Rhythmicity Score Explorer）計算，對接長庚肝病臨床巨量資料庫（CGRD）與病患組織檢體，建構出全台首創的「後B肝時間標靶醫療精準預測平台」。能在海量臨床數據中直接解讀具備 24 小時動態波動的時間靶點。開發「時間定向給藥策略（Chronotherapy）」，評估抗癌標靶藥物、發炎抑制劑在一天之中哪一個「時間窗口」給予，最能順應肝臟時鐘基因的節律，進而在極大化毒殺癌前病變細胞的同時，利用時間差完美避開對正常肝細胞線粒體造成的毒性。將臨床大數據與基礎分子生物學實驗無縫對接。

總結

本研究室是一個高度聚焦於「時間（Time）」與「倍性（Ploidy）」雙重維度的前沿轉譯醫學實驗室。我們的研究不僅重新定義了晝夜節律失調引發肝癌的演化路徑，更透過建立多倍體逆轉與時間藥理學平台，為未來臨床上慢性肝病與肝癌前期病變的「精準時間醫療」提供了新思維的解決方案。

參考資料

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)

近期發表論文

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)