Rhodioloside of Hong Huang decoction alleviates the doxorubicin-induced cardiotoxicity via the LINC00339/FOXO3A pathway

Q: What are the key findings of this study?

Rhodioloside and Hong Huang decoction significantly attenuated doxorubicin-induced cardiotoxicity and cardiomyocyte apoptosis via the LINC00339/FOXO3A signaling pathway (P<0.001).

Q: What is the clinical evidence from this study?

Population: Doxorubicin-induced cardiotoxicity in breast cancer. Intervention: Hong Huang decoction (HHD) and Rhodioloside vs. Doxorubicin alone (2.5 mg/kg/week) or Dexrazoxane. Primary outcome: FOXO3A and apoptotic signaling protein expression (FOXO3A, p-FOXO3A, cleaved-caspase-3, BCL-2) in myocardial tissue and H9C2 cells (p=<0.001).

Q: What does this research mean for the field?

Rhodioloside from Hong Huang decoction attenuates doxorubicin-induced cardiotoxicity and cardiomyocyte apoptosis via modulation of the LINC00339/FOXO3A signaling pathway. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Q: What question did this study set out to answer?

To evaluate the cardioprotective effects of Hong Huang decoction and identify how its constituent rhodioloside mitigates doxorubicin-induced cardiotoxicity.

Bei Ye; Wenhao Mao; Jingxian Xue

doi:10.21203/rs.3.rs-11103615/v1

October 26, 2026Open Access

Rhodioloside of Hong Huang decoction alleviates the doxorubicin-induced cardiotoxicity via the LINC00339/FOXO3A pathway

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Key result

Rhodioloside and Hong Huang decoction attenuate doxorubicin cardiotoxicity and cardiomyocyte apoptosis via LINC00339/FOXO3A signaling.

P<0.001

Why the study?

Doxorubicin causes dose-dependent cardiotoxicity that limits its clinical use in breast cancer chemotherapy. Although Hong Huang decoction has shown cardioprotective effects during doxorubicin treatment, its underlying mechanism and active constituents remained unclear.

Does Rhodioloside (from Hong Huang decoction) attenuate doxorubicin-induced cardiotoxicity and apoptosis via the LINC00339/FOXO3A signaling pathway in tumor-bearing mice and H9C2 cardiomyocytes?

Key Points

To evaluate the cardioprotective effects of Hong Huang decoction and identify how its constituent rhodioloside mitigates doxorubicin-induced cardiotoxicity.
Analyzed Hong Huang decoction constituents using high-performance liquid chromatography with diode-array detection (HPLC-DAD).
Assessed myocardial tissue, cardiac short-axis dimensions at week 6, and oxidative stress markers (ROS, SOD, NO) in doxorubicin-treated tumor-bearing mice.
Investigated FOXO3A and apoptotic markers in H9C2 cells and left ventricular anterior wall tissue using Western blotting, qRT-PCR, RIP-seq, and LINC00339 gain- and loss-of-function assays.
Rhodioloside co-treatment preserved myocardial wall structure and cardiac short-axis dimension without diminishing doxorubicin antitumor efficacy in mice, while reducing ROS and increasing SOD and NO levels.
In mice, rhodioloside co-treatment significantly reduced FOXO3A and cleaved-caspase-3 while increasing p-FOXO3A and BCL-2 compared to doxorubicin alone (all P < 0.001).
LINC00339 was enriched in FOXO3A immunoprecipitates; LINC00339 knockdown reversed doxorubicin-induced alterations in FOXO3A and apoptotic markers (all P < 0.001 vs doxorubicin alone), whereas LINC00339 overexpression significantly increased FOXO3A and cleaved-caspase-3 (both P < 0.001 vs rhodioloside alone).

Structured PICO

Does Rhodioloside (from Hong Huang decoction) attenuate doxorubicin-induced cardiotoxicity and apoptosis via the LINC00339/FOXO3A signaling pathway in tumor-bearing mice and H9C2 cardiomyocytes?

P

Population

Female BALB/c nude mice (6-8 weeks old) bearing MDA-MB-231 breast cancer tumors and H9C2 cells treated with doxorubicin for up to 8 weeks.

I

Intervention

Hong Huang decoction (HHD; concentrated to 0.92 g/mL from Astragalus mongholicus 30 g, Rhodiola rosea 10 g, Curcuma wenyujin 10 g, Rheum palmatum 6 g) or its bioactive constituent Rhodioloside (Rho), as well as LINC00339-shRNA, LINC00339-overexpression, and FOXO3A-shRNA vectors in vitro, co-administered with intraperitoneal doxorubicin (2.5 mg/kg once weekly).

C

Comparator

Doxorubicin-only control (2.5 mg/kg intraperitoneally once weekly), dexrazoxane (Dex) plus doxorubicin, and untreated control.

O

Outcome

Myocardial apoptosis, oxidative stress markers (ROS, SOD, NO), and AKT/FOXO3A/LINC00339 signaling protein and RNA expression (FOXO3A, p-FOXO3A, AKT1, AKT2, p-AKT, cleaved caspase-3, caspase-8, BAX, BAK, BCL-2) at 6 weeks.surrogate

Main Result

p-value: p=<0.001

This preclinical study identifies Rhodioloside as a bioactive component of Hong Huang decoction that mitigates doxorubicin-induced cardiotoxicity and cardiomyocyte apoptosis via modulation of the LINC00339/FOXO3A pathway without impairing antitumor efficacy.

Limitations

Preclinical study restricted to animal models (tumor-bearing mice) and in vitro cell lines (H9C2)
Combined LINC00339 knockdown and Rhodioloside treatment did not uniformly produce additive improvements across all downstream apoptotic markers
Potential anti-tumor properties of Rhodioloside observed in mice require further investigation to validate
For Figs. 1 and 4, target-protein signals were normalized using the corresponding group mean beta-actin densitometric value because only group-level beta-actin values were available for these datasets.

Implication

Hypothesis-generating for rhodioloside in doxorubicin cardiotoxicity; leaves open clinical translation from animal models.

Abstract

Background Doxorubicin (DOX) is widely used in breast cancer chemotherapy, but its dose-dependent cardiotoxicity limits clinical application. Hong Huang decoction (HHD) has been reported to exert cardioprotective effects during DOX treatment, although the underlying mechanism remains unclear. This study investigated the cardioprotective effects of HHD and the potential mechanism by which its bioactive constituent Rhodioloside modulates DOX-induced cardiotoxicity. Methods The protective effects of HHD on DOX-induced cardiotoxicity were evaluated in tumor-bearing mice. HHD constituents were characterized by high-performance liquid chromatography with diode-array detection (HPLC-DAD). The effects and mechanism of Rhodioloside were further investigated in tumor-bearing mice and H9C2 cells using biochemical assays, Western blotting, qRT-PCR, RIP-seq, and gain- and loss-of-function experiments. Results HPLC-DAD identified Rhodioloside in HHD. Rhodioloside attenuated DOX-induced oxidative stress and apoptosis and modulated FOXO3A-associated signaling. LINC00339 knockdown and Rhodioloside each attenuated DOX-associated changes in FOXO3A signaling. Their combination further reduced FOXO3A expression but did not consistently produce additional improvement across all downstream apoptotic markers. LINC00339 overexpression markedly attenuated the signaling response associated with Rhodioloside. Conclusion Rhodioloside may represent a bioactive component of HHD and may alleviate DOX-induced cardiotoxicity, at least in part, through modulation of LINC00339/FOXO3A-associated signaling.

Discussion

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Cite This Study

Ye et al. (2026) studied Doxorubicin-induced cardiotoxicity in breast cancer. Hong Huang decoction (HHD) and Rhodioloside vs. Doxorubicin alone (2.5 mg/kg/week) or Dexrazoxane was evaluated on FOXO3A and apoptotic signaling protein expression (FOXO3A, p-FOXO3A, cleaved-caspase-3, BCL-2) in myocardial tissue and H9C2 cells (p=<0.001). Rhodioloside and Hong Huang decoction significantly attenuated doxorubicin-induced cardiotoxicity and cardiomyocyte apoptosis via the LINC00339/FOXO3A signaling pathway (P<0.001).

synapsesocial.com/papers/6ae1273426fed725aca6d8d4 https://doi.org/10.21203/rs.3.rs-11103615/v1

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Rhodioloside of Hong Huang decoction alleviates the doxorubicin-induced cardiotoxicity via the LINC00339/FOXO3A pathway

Key Points

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

Rhodioloside of Hong Huang decoction alleviates the doxorubicin-induced cardiotoxicity via the LINC00339/FOXO3A pathway

Key Points

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

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