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J. Adv. Res., Jul 03 2025, S2090-1232(25)00499-0 | https://doi.org/10.1016/j.jare.2025.07.001 Scutellarein attenuates cancer cachexia-induced muscle atrophy via targeted inhibition of the JAK/STAT pathway

Heeju Ahn ^a,1, Heeju Kim ^b,1, Yeyoung Yoon ^a, Minju Jeong ^b, Sieun Lee ^c, Peng Chen ^d, Keke Wang^e, Sujung Park ^a, Jae Hwan Kim ^b, Jiyun Ahn^f,g, Qiantao Wang^d, Yoonhee Jin^c, Young Jin Jang ^a, Sanguine Byun^b,h

^aDepartment of Food Science and Technology, Seoul Women’s University, Seoul 01797, Republic of Korea
^bDepartment of Biotechnology, Yonsei University, Seoul 03722, Republic of Korea
^cDepartment of Physiology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
^dWest China School of Pharmacy, Sichuan University, Chengdu 610041, China
^eChina-US (Henan) Hormel Cancer Institute, Zhengzhou 450003, China
^fAging Research Group, Korea Food Research Institute, Wanju-gun 55365, Republic of Korea
^gDivision of Food Biotechnology, University of Science and Technology, Daejeon 34113, Republic of Korea
^hPOSTECH Biotech Center, Pohang University of Science and Technology (POSTECH), Pohang 37673, Republic of Korea

Corresponding authors: Young Jin Jang, Sanguine Byun

Abstract

Introduction
Cancer cachexia is a multifaceted metabolic syndrome characterized by severe loss of skeletal muscle and adipose tissue, diminishing both quality of life and survival in cancer patients. Despite its prevalence, effective treatments for cancer cachexia remain limited. The JAK/STAT signaling pathway has been identified as a key driver of muscle atrophy in cachexia.

Objectives
This study aimed to investigate the therapeutic potential of scutellarein, a natural compound, as a JAK kinase inhibitor to prevent and mitigate cancer cachexia-induced muscle atrophy.

Methods
In vitro experiments were conducted using the mouse myoblast cell line C2C12 and human induced pluripotent stem cell (iPSC)-derived skeletal muscle cells. Myotube atrophy was induced using IFN-γ/TNF-α and cancer cell-conditioned media. Two independent mouse models of cancer cachexia were utilized for in vivo analysis. Muscle tissues were examined through transcriptomic and molecular analyses, including RNA sequencing, PCR, and immunoblotting. Structure-activity relationship studies and molecular docking analyses were performed to investigate the binding interaction of scutellarein with JAK kinases.

Results
Through a chemical library screen, we identified scutellarein as a potent JAK kinase inhibitor. Scutellarein effectively mitigated myotube atrophy by inhibiting protein degradation and promoting protein synthesis in C2C12 and iPSC-derived muscle cells. In two distinct mouse models of cancer cachexia, scutellarein treatment significantly reduced muscle wasting, improved muscle strength and function, and countered fat depletion. Transcriptomic and molecular analyses of muscle tissues further demonstrated that scutellarein inhibited activation of JAK/STAT pathways and restored suppression of myogenesis and mitochondrial biogenesis. Structure-activity relationship analyses further revealed critical hydroxyl group positions essential for JAK binding.

Conclusion
Collectively, our findings suggest scutellarein as a promising candidate for the prevention and treatment of cancer cachexia, providing a novel therapeutic approach to address this critical unmet need in cancer care.

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