Background
Sepsis, a life-threatening condition caused by dysregulated host response to infection, remains a major cause of global mortality. Sepsis-induced cardiac dysfunction (SICD), also known as septic cardiomyopathy, significantly worsens patient outcomes and lacks targeted therapies. Although inflammation and metabolic disruption are known contributors, the precise molecular mechanisms driving SICD remain poorly understood, hampering the development of effective treatments.
The kinesin family member 13B (KIF13B) has recently emerged as a regulator of cellular lipid metabolism in the liver, but its role in the heart, especially under septic conditions, was unknown. Given the heart’s high dependence on fatty acid oxidation for energy, researchers hypothesized that KIF13B might protect cardiac function during sepsis by maintaining lipid homeostasis.

Research Progress
To investigate the role of KIF13B in SICD, a research team led by Prof. Xunde Xian from Peking University conducted a series of experiments using mouse models of sepsis and cultured cardiomyocytes. The team first showed that KIF13B expression was significantly downregulated in the hearts of septic mice (Fig.1). They then used global Kif13b knockout mice to examine the functional consequences of KIF13B loss.

Results revealed that Kif13b deficiency exacerbated sepsis-induced cardiac dysfunction, leading to reduced survival, increased lipid accumulation, heightened fibrosis, and impaired mitochondrial respiration. Through lipidomics and transcriptomics, the team found that KIF13B loss disrupted oxidative phosphorylation and elevated toxic lipid species in the heart (Fig.2).

Mechanistically, the researchers discovered that KIF13B physically interacts with the lipid droplet protein Perilipin 5 (PLIN5), preventing its degradation in lysosomes and promoting its localization near mitochondria. To further explore the underlying mechanism, the team knocked down Kif13b in primary neonatal rat cardiomyocytes (NRCMs) and found that this exacerbated LPS-induced lipid deposition and mitochondrial dysfunction. Conversely, overexpressing KIF13B effectively alleviated these pathological phenotypes (Fig.3, Fig.4).

To identify the downstream molecular mechanism, they combined proteomic screening and found that the lipid metabolism-related protein PLIN5 was the most significantly altered in Kif13b-deficient hearts. Experiments confirmed that restoring PLIN5 expression in the absence of KIF13B effectively mitigated LPS-induced lipid accumulation and mitochondrial dysfunction. In contrast, knocking down Plin5 abolished the protective effect of KIF13B overexpression, indicating that PLIN5 acts downstream of KIF13B as a key effector (Fig.5).

Further mechanistic studies revealed that KIF13B directly binds to PLIN5. Loss of KIF13B led to decreased PLIN5 protein levels due to enhanced degradation via the lysosomal pathway. Moreover, KIF13B promoted the mitochondrial–lipid droplet localization of PLIN5, thereby enhancing lipid utilization (Fig.6).

Most importantly, the team demonstrated that cardiac-targeted gene therapy using an AAV9 vector to restore PLIN5 could reverse cardiac dysfunction, reduce lipid accumulation, and improve outcomes in septic Kif13b-deficient mice, confirming the therapeutic potential of targeting this axis (Fig.7).

Future Prospects
The identification of the KIF13B–PLIN5 axis opens new avenues for treating septic cardiomyopathy. Reduced cardiac KIF13B could serve as a biomarker for SICD, while enhancing PLIN5 activity—via gene therapy or small-molecule stabilizers—may offer a targeted metabolic therapy alongside conventional anti-inflammatory approaches.
This study provides the first evidence that motor protein KIF13B plays a protective role in cardiac lipid homeostasis during sepsis(Fig.8). Further research may explore pharmacological strategies to strengthen the KIF13B–PLIN5 interaction, potentially leading to novel therapies for sepsis-induced heart failure. Moreover, these findings may also inform therapeutic strategies for other cardiac conditions characterized by lipid metabolic disturbances.

The complete study is accessible via DOI:10.34133/research.1033