Background

Diabetic nephropathy (DN) is one of the most common microvascular complications of diabetes and a leading cause of end-stage renal disease (ESRD). Its typical pathological manifestations include glomerulosclerosis, tubulointerstitial fibrosis, and impaired tubular epithelial function [1]. In recent years, research perspectives have gradually shifted from the isolated “glomerulus-centered” or “tubule-centered” single model to a holistic pathogenic framework, which highlights the synergistic injury between glomerular podocytes and renal tubular epithelial cells throughout DN progression. Cumulative evidence indicates that early podocyte lesions initiate downstream tubular metabolic stress, while progressive tubular fibrosis further aggravates glomerular filtration dysfunction; structural and functional defects of both renal compartments jointly determine disease prognosis [2,3].

At the mitochondrial functional level, both glomerular podocytes and proximal tubule epithelial cells depend on intact mitochondrial homeostasis to sustain their specialized physiological functions, yet they display distinct susceptibility to diabetic lipotoxicity and hypoxia [4]. Prior investigations have frequently observed disrupted mitochondrial quality control, endoplasmic reticulum stress and aberrant mitochondrial apoptotic signaling in both injured glomeruli and tubules of DN patients [5,6]. As core organelles governing cellular energy metabolism and cell survival, mitochondria rely on precise quality control systems to maintain cellular balance. Mitophagy, a subtype of selective autophagy responsible for eliminating damaged mitochondria, may serve as an important shared regulatory module across renal compartments, and its abnormal activity is speculated to participate in the mutual exacerbation of glomerular and tubular lesions in DN [7].

FUN14 domain-containing protein 1 (FUNDC1) is an outer mitochondrial membrane mitophagy receptor, which initiates LC3-dependent mitochondrial clearance under hypoxic and metabolic stress conditions [8]. Existing preclinical and clinical studies have implicated FUNDC1-mediated mitophagy in the progression of diabetic microvascular complications and acute renal injury [9,10]. In acute kidney injury models, FUNDC1 activation appears to relieve tubular oxidative stress and epithelial apoptosis [11]. Nevertheless, whether FUNDC1 participates in the synergistic pathogenic cascade of chronic DN, and how its regulatory network differs or coordinates between glomerular and tubular compartments, remains largely unclear.

From the analytical perspective, transcriptome profiling combined with network pharmacology can systematically decode complex gene interaction networks, which has been widely adopted to screen potential pathogenic hub molecules. Summary-data-based Mendelian randomization (SMR), a genetic association analysis tool, can partially mitigate confounding bias and reverse causality inherent to observational tissue research, offering suggestive population-level evidence for gene–disease associations [12]. In the present work, we set gene expression levels as exposure and DN disease susceptibility as outcome to infer potential genetic correlations. The combinatorial analytical strategy of compartmental transcriptomics, SMR and network pharmacology enables multi-dimensional exploration of mitochondrial regulatory signatures from genetic causality, molecular interaction and tissue-specific pathway layers.

Based on the above background, we integrated independent glomerular bulk transcriptome and high-purity spatial tubular transcriptomic cohorts, combined with SMR genetic inference and network pharmacology, to characterize the potential regulatory role of FUNDC1 in DN-associated mitochondrial impairment. We further aimed to screen key hub molecules mediating FUNDC1-related mitochondrial homeostasis, and explore the shared and compartment-specific transcriptional patterns of this mitophagy-lipid metabolic axis across glomerular and tubular compartments. This work may provide preliminary mechanistic clues explaining the coordinated progression of glomerular and tubular injury in DN, and uncover candidate genes with suggestive genetic correlation and prospective therapeutic value (Fig. 1).

Fig. 1: Research design.