Objective:

2

To elucidate the therapeutic effect and mechanism of Compound Danshen Dripping Pill (CDDP) on cardiotoxicity caused by doxorubicin (DOX) and trastuzumab (TRZ).

Methods:

2

Eighteen Sprague-Dawley (SD) rats were randomly divided into the normal group (normal saline)

the model group (DOX/TRZ)

and CDDP administration group (DOX/TRZ+CDDP)

by a random number table

with 6 rats in each group. Rats were administered either DOX or saline via tail vein injection 6 times over an 11-day period. One week later

they received either TRZ or saline via intraperitoneal injection 6 times over another 11-day period. All rats received CDDP or saline via oral gavage continuously for 36 days. Then

echocardiography was performed on the rats

and biochemical parameters of blood and heart samples were determined. Rats' feces were taken for intestinal flora testing and plasma metabolites were analyzed using untargeted metabolomics.

Results:

2

Echocardiographic assessment in rats demonstrated that DOX/TRZ induced cardiac dysfunction

whereas CDDP significantly ameliorated this impairment(

P

<

0.05 or

P

<

0.01). Furthermore

results revealed that DOX/TRZ elevated cardiac injury indicators (left ventricular ejection fraction

fractional shortening

cardiac troponin I

creatine kinase

creatine kinase-MB)

while CDDP treatment significantly reduced these levels (

P

<

0.05 or

P

<

0.01). Plasma metabolite analysis revealed enrichment in tryptophan metabolism

tricarboxylic acid cycle

and phenylalanine metabolism. Intestinal microbiota analysis showed increased richness and altered abundance of certain bacteria (

Clostridia_UCG-014

and

Lactobacillus

) with CDDP treatment.

Conclusions:

2

CDDP can prevent and protect against DOX/TRZ-induced cardiac injury. It influences tryptophan metabolism by modulating

Clostridia_UCG-014

abundance

inhibits indole-3-carboxylic acid levels

increases kynurenine levels

thereby exerting anti-cardiotoxic effects.