Targeting PDE2A of macrophages attenuates sorafenib-induced cardiotoxicity

Q: What are the key findings of this study?

Pharmacological or genetic inhibition of macrophage PDE2A attenuated sorafenib-induced cardiac dysfunction and inflammatory remodeling while enhancing anti-tumor efficacy in murine models.

Q: What is the clinical evidence from this study?

Population: Sorafenib-induced cardiotoxicity (preclinical murine and cellular models). Intervention: PDE2A inhibition (BAY60-7550 or shRNA knockdown) or macrophage depletion (PLX3397) vs. Sorafenib alone (100 mg/kg or 120 mg/kg daily oral gavage in vivo; 5 µM for 24-48 h in vitro) or vehicle control. Primary outcome: Sorafenib-induced cardiotoxicity (left ventricular ejection fraction, fractional shortening, myocardial injury biomarkers, and macrophage inflammatory remodeling) (p=<0.05).

Q: What does this research mean for the field?

Pharmacological or genetic inhibition of macrophage PDE2A attenuates sorafenib-induced cardiotoxicity through cGMP/PKG signaling without compromising anti-tumor efficacy. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

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

To define the role of cardiac macrophages in sorafenib-induced cardiotoxicity and evaluate whether targeting phosphodiesterase 2A (PDE2A) can alleviate myocardial damage.

Sijia Li; Shuangli Zhu; Kai Fu; Can Pan; Yuelu Lan; Xueping Wang; Xin Su; Zhangqi Cao; Fang Wang; Liwu Fu

doi:10.1186/s12916-026-05404-8

November 14, 2026BMC MedicineOpen Access

Targeting PDE2A of macrophages attenuates sorafenib-induced cardiotoxicity

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Key result

Macrophage PDE2A inhibition attenuates sorafenib-induced cardiotoxicity while enhancing anti-tumor efficacy in mice.

P<0.05

Why the study?

Sorafenib is associated with clinically relevant cardiotoxicity, but the underlying mechanisms and the role of cardiac macrophages in sorafenib-induced cardiotoxicity remain incompletely understood.

Does targeting macrophage PDE2A via genetic knockdown or pharmacological inhibition (BAY60-7550) attenuate sorafenib-induced cardiotoxicity and inflammatory remodeling in murine and cellular models?

Key Points

To define the role of cardiac macrophages in sorafenib-induced cardiotoxicity and evaluate whether targeting phosphodiesterase 2A (PDE2A) can alleviate myocardial damage.
In vivo cardiotoxicity was modeled in male C57BL/6J mice via daily oral gavage of sorafenib at 100 mg/kg for 28 consecutive days, alongside macrophage depletion with PLX3397 (10 mg/kg every 48 h) or PDE2A inhibition with BAY60-7550 (3 mg/kg every other day).
Subcutaneous Hepa1-6 tumor-bearing mouse models were treated with daily sorafenib (120 mg/kg) and BAY60-7550 (3 mg/kg every other day) to assess tumor growth.
In vitro Transwell co-cultures of RAW264.7 macrophages and HL-1 cardiomyocytes were exposed to 5 µM sorafenib for 24 h with or without BAY60-7550, DT-2, PKI, 8-Br-cGMP, or 8-Br-cAMP, followed by viability, ROS, JC-1, and transcriptomic analyses (n=3 per group).
Sorafenib induced cardiac dysfunction, myocardial vacuolar degeneration, and inflammatory remodeling in vivo, driven by increased macrophage infiltration and shift toward a pro-inflammatory phenotype, while PLX3397-mediated macrophage depletion attenuated cardiotoxicity.
Transcriptomic profiling identified PDE2A upregulation in sorafenib-injured hearts, localized primarily to macrophages rather than cardiomyocytes.
Pharmacological inhibition of PDE2A with BAY60-7550 or genetic knockdown attenuated cardiomyocyte oxidative stress and mitochondrial dysfunction via cGMP/PKG signaling, reduced cardiac injury in vivo, and enhanced antitumor suppression in Hepa1-6 tumor-bearing mice.

Structured PICO

Does targeting macrophage PDE2A via genetic knockdown or pharmacological inhibition (BAY60-7550) attenuate sorafenib-induced cardiotoxicity and inflammatory remodeling in murine and cellular models?

P

Population

Preclinical study in 6-8-week-old male C57BL/6J mice (including Hepa1-6 tumor-bearing mice) and indirect RAW264.7 macrophage-HL-1 cardiomyocyte co-cultures exposed to sorafenib for up to 28 days.

I

Intervention

Pharmacological PDE2A inhibition with BAY60-7550 (3 mg/kg intraperitoneally every other day in vivo; 5 µM in vitro), genetic PDE2A knockdown in macrophages via shRNA, or macrophage depletion with CSF1R inhibitor PLX3397 (10 mg/kg intraperitoneally every 48 hours) co-administered with sorafenib (100 mg/kg/day orally for 28 days in non-tumor mice, 120 mg/kg/day orally in tumor-bearing mice, or 5 µM for 24 hours in vitro).

C

Comparator

Sorafenib monotherapy (100 mg/kg or 120 mg/kg daily oral gavage in vivo; 5 µM in vitro) and vehicle-treated control groups.

O

Outcome

Attenuation of sorafenib-induced cardiotoxicity assessed by echocardiography (LVEF, FS, LVIDs, LVIDd), serum/supernatant myocardial injury biomarkers (CK-MB, cTnT, pro-BNP, LDH), cardiac histopathology (H&E vacuolation, Masson's trichrome fibrosis, WGA cross-sectional area), and macrophage infiltration/polarization (M1 CD80+/CD86+ vs M2 CD206+).surrogate

Main Result

p-value: p=<0.05

Identifies macrophage PDE2A as a key mediator of sorafenib-induced cardiotoxicity and demonstrates that pharmacological PDE2A inhibition (BAY60-7550) protects against cardiac injury while enhancing sorafenib's anti-tumor efficacy in preclinical models.

Limitations

Preclinical study restricted to murine models (C57BL/6J mice) and immortalized murine cell lines (HL-1, RAW264.7, Hepa1-6)
Small biological replicate sample sizes per group (n=3 for in vitro and RNA-seq; n=5 to 8 per group for in vivo cohorts)
Only male mice were used in the in vivo experiments
Preclinical in vitro and in vivo mouse study; findings are not yet validated in human patients
Only male C57BL/6J mice (6-8 weeks old) were evaluated
Limited sample size in RNA-seq and in vitro experiments (n=3 biological replicates per group) where formal normality testing was omitted

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Implication

PDE2A inhibition merits investigation in sorafenib-treated patients; leaves open clinical translation pending prospective trials.

Abstract

Sorafenib, a multi-kinase inhibitor widely used in hepatocellular carcinoma, is associated with clinically relevant cardiotoxicity, but the underlying mechanisms remain incompletely understood. Cardiac macrophages are key regulators of inflammatory injury in the heart; however, their role in sorafenib-induced cardiotoxicity (SIC) has not been fully defined. A murine model of SIC was established in C57BL/6J mice. Indirect macrophage-cardiomyocyte co-culture systems were used for in vitro mechanistic studies. Macrophages were depleted in vivo using PLX3397. Transcriptomic profiling was performed to identify candidate mediators associated with macrophage-related SIC. PDE2A was further investigated using genetic knockdown and pharmacological inhibition in cellular and animal models. Sorafenib induced cardiac dysfunction, myocardial injury, and inflammatory remodeling in vivo, accompanied by increased cardiac macrophage infiltration and a shift toward a pro-inflammatory phenotype. In vitro, macrophages exacerbated sorafenib-induced cardiomyocyte injury, oxidative stress, and mitochondrial dysfunction, whereas macrophage depletion attenuated SIC in vivo. Transcriptomic analysis identified PDE2A as an upregulated candidate in sorafenib-injured hearts, and this increase was reduced by macrophage depletion. PDE2A expression was preferentially increased in macrophages rather than cardiomyocytes under sorafenib exposure. Genetic or pharmacological inhibition of PDE2A attenuated injury-related phenotypes and inflammatory activation in vitro and alleviated SIC in vivo. Mechanistically, these effects were predominantly associated with cGMP/PKG signaling. In tumor-bearing models, BAY60-7550 was associated with enhanced tumor suppression. These findings indicate that sorafenib-induced cardiotoxicity is closely associated with macrophage-driven inflammatory remodeling and identify PDE2A as a candidate mediator of this process. Pharmacological inhibition of PDE2A attenuated cardiac injury while maintaining, and potentially enhancing, the anti-tumor activity of sorafenib, supporting PDE2A as a potential therapeutic target in this setting.

Discussion

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Cite This Study

Li et al. (2026) studied Sorafenib-induced cardiotoxicity (preclinical murine and cellular models). PDE2A inhibition (BAY60-7550 or shRNA knockdown) or macrophage depletion (PLX3397) vs. Sorafenib alone (100 mg/kg or 120 mg/kg daily oral gavage in vivo; 5 µM for 24-48 h in vitro) or vehicle control was evaluated on Sorafenib-induced cardiotoxicity (left ventricular ejection fraction, fractional shortening, myocardial injury biomarkers, and macrophage inflammatory remodeling) (p=<0.05). Pharmacological or genetic inhibition of macrophage PDE2A attenuated sorafenib-induced cardiac dysfunction and inflammatory remodeling while enhancing anti-tumor efficacy in murine models.

synapsesocial.com/papers/6af9ebcdd393cbc380a04ff6 https://doi.org/10.1186/s12916-026-05404-8

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Targeting PDE2A of macrophages attenuates sorafenib-induced cardiotoxicity

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Targeting PDE2A of macrophages attenuates sorafenib-induced cardiotoxicity

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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