Single-Cell Analyses Reveal IKKα Regulates the Interaction Between Macrophages and T Cells in the Doxorubicin-Induced Cardiomyopathy

Q: What is the clinical evidence from this study?

Population: Doxorubicin-induced cardiomyopathy in mouse model. Intervention: Macrophage-specific IKKα knockout (IKKα Lyz2-Cre) vs IKKα flox/flox control vs. IKKα flox/flox mice with same DOX dosing. Primary outcome: Cardiac function assessed by left ventricular ejection fraction (EF%) and fractional shortening (FS%), cardiac fibrosis, inflammatory cytokine levels.

Q: What does this research mean for the field?

IKKα regulates the interaction between macrophages and T cells, influencing the severity of doxorubicin-induced cardiomyopathy. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Ganyi Chen; Yiwei Yao; Yunfei Jiang; Haoyu Qi; Yiming Liu; Li Yin; Jian Li; Yide Cao; Xi Chen; Yifan Zhu; Shengchen Liu; Zhonghao Tao

doi:10.1007/s10753-025-02365-7

February 23, 2026InflammationOpen Access

Single-Cell Analyses Reveal IKKα Regulates the Interaction Between Macrophages and T Cells in the Doxorubicin-Induced Cardiomyopathy

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Key result

Macrophage-specific IKKα knockout worsens doxorubicin-induced cardiac dysfunction and fibrosis in mice.

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Why the study?

Doxorubicin-induced cardiomyopathy causes severe cardiac impairment, and while immune cells are implicated in cardiovascular inflammation, the underlying molecular mechanisms remain unclear.

Does macrophage-specific IKKα knockout exacerbate doxorubicin-induced cardiomyopathy in mice?

Key Points

To elucidate how macrophage IKKα influences cardiac function and regulates intercellular communication with T cells during early-stage doxorubicin-induced cardiomyopathy.
Assessed cardiac function, myocardial fibrosis, and cytokine production in IKKαflox/flox and myeloid-deficient IKKαLyz2-Cre mice within one week of doxorubicin administration.
Conducted single-cell RNA sequencing on cardiac tissue, obtaining 20,052 high-quality single cells and isolating 4,547 immune cells across 11 cell types.
Characterized sub-clustering, pseudotime differentiation trajectories, and ligand-receptor interactions among monocyte-macrophage and T cell subsets using CellChat and CellPhoneDB.
IKKαLyz2-Cre mice demonstrated heightened susceptibility to doxorubicin-induced cardiotoxicity relative to IKKαflox/flox mice, with marked cardiac dysfunction, extensive fibrosis, and elevated inflammatory factors.
IKKα deletion shifted monocyte differentiation from reparative Fcna+ M2 macrophages to inflammatory Jaml+ M1 macrophages displaying upregulated NF-κB, IL-6, and IFN-γ signaling.
IKKα deficiency impaired T cell differentiation, leaving T cells in a naive T_Ccr7 state and weakening CXCL, ICOS, and MHC-I signaling pathways required for effector activation.

Structured PICO

Does macrophage-specific IKKα knockout exacerbate doxorubicin-induced cardiomyopathy in mice?

P

Population

8-week-old IKKαflox/flox and IKKαLyz2-Cre (macrophage IKKα knockout) mice, weighing 23-25 g

I

Intervention

Macrophage-specific IKKα knockout (IKKαLyz2-Cre) with doxorubicin 3 mg/kg intraperitoneally 7 times over 2 weeks

C

Comparator

IKKαflox/flox mice with doxorubicin 3 mg/kg intraperitoneally 7 times over 2 weeks

O

Outcome

Cardiac function (left ventricular ejection fraction and fractional shortening) and histological cardiac fibrosis evaluated up to 4 weekssurrogate

Macrophage-specific IKKα knockout exacerbates early-stage doxorubicin-induced cardiomyopathy by promoting a pro-inflammatory M1 macrophage shift and altering T cell interactions.

Limitations

Study conducted in mice; results may not translate directly to humans
Exact quantitative data on cardiac function and fibrosis not provided
Sample size and power calculations not described
Short-term follow-up focused on early stage cardiomyopathy only

Implication

Macrophage IKKα may protect against doxorubicin cardiotoxicity in mice; hypothesis-generating for targeted therapies pending human validation.

Abstract

Doxorubicin (DOX) is a chemotherapeutic agent used to treat solid tumors and hematologic malignancies, though DOX-induced cardiomyopathy poses a risk of severe cardiac impairment and poor prognosis. Immune cells have been increasingly implicated in cardiovascular inflammation, with overproduction of inflammatory cytokines and macrophage accumulation. However, its molecular mechanism remains unclear and needs to be further investigated. This study investigated the involvement of IKKα in regulating cardiac function in response to early-stage DOX stimulation. Results indicated that IKKαLyz2-Cre mice were more susceptible to DOX-induced cardiac injury than IKKαflox/flox mice, showing reduced heart function, extensive cardiac fibrosis, and elevated inflammatory markers. Single-cell transcriptomic analysis revealed cellular heterogeneity in DOX-induced cardiomyopathy tissue between IKKαflox/flox and IKKαLyz2-Cre mice, identifying 11 cell types, 8 of which were immune cells. Bar plots and cell density analysis showed a higher proportion of T cells in IKKαflox/floxmice, while IKKαLyz2-Cre mice had increased monocytes and macrophages. Notably, IKKα deletion promoted a shift in macrophage polarization from Fcna⁺ M2 to Jaml⁺ M1 and impaired T cell activation and differentiation. Additionally, IKKα played a critical role in mediating macrophage-T cell interactions. Loss of macrophage IKKα activated T cells through Jaml⁺ M1 macrophage, and activated T cells subsequently enhanced M1 macrophage activation via IFN-γ and IL-6. These findings highlight the potential of targeting immune cell interactions as a therapeutic strategy.

Discussion

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Cite This Study

Chen et al. (2026) studied Doxorubicin-induced cardiomyopathy in mouse model. Macrophage-specific IKKα knockout (IKKα Lyz2-Cre) vs IKKα flox/flox control vs. IKKα flox/flox mice with same DOX dosing was evaluated on Cardiac function assessed by left ventricular ejection fraction (EF%) and fractional shortening (FS%), cardiac fibrosis, inflammatory cytokine levels. Macrophage-specific IKKα knockout mice showed greater early decline in cardiac function, increased fibrosis, and elevated inflammatory markers compared to control mice after doxorubicin administration.

synapsesocial.com/papers/699e91d7f5123be5ed04f959 https://doi.org/10.1007/s10753-025-02365-7

Topics

Cardiomyopathy

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Single-Cell Analyses Reveal IKKα Regulates the Interaction Between Macrophages and T Cells in the Doxorubicin-Induced Cardiomyopathy

Figures

Key Points

Structured PICO

Limitations

Implication

Abstract

Discussion

Cite This Study

Topics

Single-Cell Analyses Reveal IKKα Regulates the Interaction Between Macrophages and T Cells in the Doxorubicin-Induced Cardiomyopathy

Figures

Key Points

Structured PICO

Limitations

Implication

Abstract

Discussion

Cite This Study

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