Lipid metabolic dysregulation in diabetic kidney disease: mechanisms, cellular impact, and therapeutic strategies

Highlights

• •Dysregulated lipid metabolism is a central mechanism driving diabetic kidney disease (DKD) onset and progression.
• •Lipid accumulation directly impairs podocytes, tubular, and mesangial cells, leading to renal dysfunction.
• •Therapies targeting lipid metabolism, including SGLT2 inhibitors and PPAR agonists, offer new strategies against DKD.

Abstract

Diabetic kidney disease (DKD) represents a prevalent and severe complication of diabetes mellitus, with growing evidence highlighting the critical role of lipid metabolic dysregulation in its pathogenesis. This review systematically examines the complex interplay between aberrant lipid metabolism and DKD progression, focusing on three major pathways: fatty acid metabolism disturbances, cholesterol homeostasis imbalance, and sphingolipid signaling alterations. We detail how these metabolic perturbations contribute to renal cell injury through multiple mechanisms, including in podocytes, tubular epithelial cells, and mesangial cells. Emerging therapeutic strategies targeting these metabolic pathways are comprehensively evaluated. Special emphasis is placed on recent advances in understanding cell-specific lipid metabolic reprogramming and its clinical implications. The review also discusses current challenges in translating these findings into clinical practice and proposes future research directions for developing personalized therapeutic approaches based on lipid metabolic profiling in DKD patients.

Introduction

Diabetic kidney disease (DKD), also referred to as diabetic nephropathy (DN), constitutes one of the most common microvascular complications of diabetes mellitus and has emerged as one of the fastest-growing subtypes of chronic kidney disease (CKD) in terms of both morbidity and mortality [1]. As the leading etiology of end-stage renal disease (ESRD) [2], DKD affects approximately 40% of type 2 diabetes patients and 30% of type 1 diabetes patients [3]. Characteristic pathological manifestations encompass glomerular basement membrane thickening, glomerulosclerosis, tubular atrophy, interstitial fibrosis, nodular glomerulosclerosis, and glomerular microaneurysm formation [4]. DKD usually progresses from an initial stage of glomerular hyperfiltration and microalbuminuria to persistent albuminuria, declining estimated glomerular filtration rate (eGFR), and progressive renal structural damage. Over time, persistent metabolic and hemodynamic stress promotes glomerulosclerosis, tubular atrophy, and tubulointerstitial fibrosis, ultimately leading to ESRD. Its insidious clinical course and the substantial costs of long-term management together contribute to a significant global disease burden.

Accumulating evidence underscores the pivotal role of dyslipidemia in the pathogenesis of various diseases, including CKD [5], [6] and DKD [7]. In DKD, insulin resistance-induced hyperglycemia and elevated fatty acid levels drive renal lipid accumulation, subsequently disrupting cholesterol and fatty acid metabolism and culminating in glomerular and tubular cell injury [6]. Additionally, the dysregulation of intracellular homeostasis due to lipid accumulation is defined as lipotoxicity, a phenomenon characterized by the activation of metabolic, inflammatory, and oxidative pathways that can ultimately lead to cell death [8]. Evidence of lipid deposition and lipotoxicity has been identified in the kidneys of patients with DKD [9]. Notably, cholesterol accumulation within cells triggers endoplasmic reticulum (ER) stress, exacerbating inflammatory responses and apoptotic signaling that damage glomerular endothelial cells [10]. Furthermore, ferroptosis – a form of regulated cell death in DKD – occurs as a direct consequence of lipid peroxidation and iron overload and demonstrates strong pathophysiological connections to impaired lipid metabolism, especially aberrant fatty acid signaling [11], [12]. DKD is considered to be associated with high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C), as dysfunctional HDL may exert detrimental effects on pancreatic β-cells and renal cells, thereby contributing to the progression of DKD [13]. Therefore, there is a strong cross-relationship between dyslipidemia and DKD, further highlighting the crucial role of lipotoxicity in renal disease.

This study aims to systematically evaluate the interplay between dysregulated lipid metabolism and DKD pathogenesis. We will particularly focus on elucidating how lipid metabolic disturbances contribute to cellular dysfunction across different renal cell populations. Through this comprehensive analysis, we seek to identify novel molecular targets for therapeutic intervention in DKD-associated lipid disorders.

Lipid metabolism abnormalities in DKD

In healthy individuals, renal tissue contains approximately 3% lipid content by wet weight [14]. Of this (by mass), more than half of the lipid content is phospholipids, which are major components of cell membranes; about one-fifth is triglycerides (TG); and about one-tenth is free fatty acids (FFAs). Emerging evidence strongly associates dyslipidemia and ectopic lipid deposition in renal tissue with the pathogenesis of kidney diseases, particularly DKD [15]. Importantly, lipotoxicity-related kidney injury is contingent not only on the quantity of lipids accumulated in the kidney, but also on the type of lipids involved [9]. Circulating levels of TG, low-density lipoprotein (LDL), and apolipoprotein B (ApoB) serve as independent risk factors for estimated glomerular filtration rate (eGFR) decline, while TG, total cholesterol (TC), and lipoprotein (a) [LP(a)] are independent risk factors for 24-hour urinary protein quantification [16]. The relationship between the non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) and CVD-related mortality in patients with DKD appears to follow a U-shaped pattern. Specifically, when NHHR is <1.82, increases in NHHR are associated with a reduced risk of CVD-related mortality; however, beyond this threshold, higher NHHR levels are associated with an elevated cardiovascular risk [17]. A Mendelian randomization study demonstrated that TG are a risk factor for both DKD and urinary albumin-to-creatinine ratio (UACR), whereas HDL-C exhibits protective effects against both; additionally, apolipoprotein A1 (ApoA1) may prevent DKD, while ApoB is a risk factor for UACR [18]. It is becoming increasingly clear that alterations in fatty acid and cholesterol metabolism play a pivotal role in the pathogenesis of renal lipid accumulation, inflammation, oxidative stress, and fibrosis [19]. Significant dysregulation of cholesterol, phospholipids, triglycerides, fatty acids, and sphingolipids has been documented in DKD, with their pathological accumulation in renal tissue being mechanistically linked to disease pathogenesis [20]. Fig. 1 schematically illustrates the metabolic pathways of fatty acids, cholesterol, and sphingolipids relevant to these processes. In DKD, hyperglycemia per se profoundly accelerates lipotoxicity by driving a vicious cycle of “glucolipotoxicity.” Elevated intracellular glucose directly activates ChREBP and upregulates SREBP-1c, which synergistically promotes de novo lipogenesis and renal lipid accumulation. Furthermore, hyperglycemia-induced oxidative stress and advanced glycation end products (AGEs) severely exacerbate lipid peroxidation, fundamentally amplifying lipid-induced cellular injury.

Fig. 1.

The Complex Crosstalk of Fatty Acid, Cholesterol, and Sphingolipid Metabolism in Renal Cells under Diabetic Kidney Disease (DKD). This schematic illustrates the intricate interactions and metabolic reprogramming of three major lipid pathways across cellular compartments. (1) Fatty Acid (FA) Metabolism (Blue): Free fatty acids (FFAs) are transported intracellularly via FATP and FABP, and enter the mitochondria through CPT1 for β-oxidation. (2) Cholesterol Metabolism (Green): Cholesterol homeostasis is governed by LDLR-mediated uptake, de novo synthesis via the ER-Golgi SREBP-2/SCAP/INSIG axis and HMGCR, and efflux primarily mediated by ABCA1, ABCG1, and SR-BI. (3) Sphingolipid Metabolism (Purple): SMPDL3b alters membrane dynamics and inhibits ceramide conversion to ceramide-1-phosphate (C1P), exacerbating pathogenic ceramide accumulation. Crucially, these distinct pathways intersect at four major pathogenic nodes (highlighted in red dashed lines): Crosstalk 1 (Receptor Overlap) identifies CD36 as a dual-function receptor mediating the simultaneous pathological influx of both FFAs and cholesterol/oxidized LDL. Crosstalk 2 (Metabolic Hub) highlights Acetyl-CoA, the end-product of FA β-oxidation, as the foundational substrate linking FA breakdown to de novo cholesterol synthesis. Crosstalk 3 (Structural Hub/Lipid Rafts) demonstrates that excess cholesterol and ceramide co-localize in the plasma membrane, disrupting lipid rafts to synergistically provoke cytoskeletal instability, impaired insulin receptor signaling, and cellular apoptosis. Crosstalk 4 (Lipotoxic Stress) illustrates how hyperglycemia and lipid overload induce profound ER stress and oxidative stress (ROS), triggering a vicious glucolipotoxic cycle by concurrently upregulating SREBP-1c and SREBP-2. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fatty acid metabolism

Free fatty acids (FFAs), essential cellular energy substrates, are initially activated into fatty acyl-CoA by acyl-CoA synthetase long-chain family member 1 (ACSL1) and subsequently transported into mitochondria via carnitine palmitoyltransferase 1 (CPT1). Within mitochondria, fatty acyl-CoA undergoes β-oxidation, yielding acetyl-CoA, a critical substrate for adenosine triphosphate (ATP) generation. When acetyl-CoA exceeds cellular energy demands, the surplus is redirected toward de novo lipogenesis, ultimately stored as triglycerides. Notably, renal lipid accumulation—a hallmark of DKD—has been linked to dysregulated fatty acid metabolism, characterized by enhanced de novo lipogenesis and impaired fatty acid oxidation. Supporting this, a longitudinal study involving over 90 American Indians with type 2 diabetes demonstrated a positive correlation between elevated serum unsaturated FFAs and DKD progression [21].

Fatty acids serve as a major energy substrate in the human body. Following cellular uptake, they are transported to mitochondria for β-oxidation, a process mediated by specialized lipid-handling proteins, including CD36 (cluster of differentiation 36), fatty acid transport proteins (FATPs), and fatty acid-binding proteins (FABPs). CD36, also known as scavenger receptor class B member 2 (SR-B2), is a transmembrane glycoprotein that facilitates fatty acid internalization. It is highly expressed in renal cells—particularly tubular epithelial cells, podocytes, and mesangial cells—and functions as a receptor for long-chain FAs and oxidized lipids [22]. Beyond lipid transport, CD36 contributes to renal lipid accumulation, pro-inflammatory signaling, and fibrotic progression [22]. Experimental evidence from murine models indicates that kidney-specific CD36 overexpression exacerbates renal lipid deposition, particularly triglycerides [23]. Notably, hyperglycemia upregulates CD36 expression, promoting apoptosis in both renal tubular epithelial cells [24], [25] and podocytes [26]. Pharmacological intervention studies suggest therapeutic potential; for instance, astragaloside IV attenuates CD36 upregulation in human glomerular mesangial cells and DKD rat models, concomitantly reducing palmitate-induced FFA accumulation, oxidative stress, and fibrosis [27]. FATPs are transmembrane proteins that are involved in the uptake and activation of FA. The FATP family comprises six tissue-specific isoforms, with FATP1, FATP2, and FATP4 being predominantly expressed in the kidney [28]. Growing evidence implicates FATPs, particularly FATP2, in dysregulated lipid uptake in DKD. Experimental studies using multiple DKD mouse models—including lepr^db/db eNOS^-/- diabetic mice, high-fat diet/low-dose streptozotocin-induced mice, and global FATP2 knockout mice—demonstrate that FATP2 mediates DKD pathogenesis through combined lipotoxic and glucotoxic (glycolipotoxic) mechanisms [29]. Another key contributor to pathological lipid accumulation in DKD is FABP, a family of small cytoplasmic chaperones that facilitate intracellular localization of long-chain FAs and bioactive lipids [30]. Clinical investigations reveal progressive elevation of plasma FABP1 and FABP2 levels with advancing DKD in type 2 diabetes patients (n = 268) [31]. Notably, serum FABP4 concentrations are increased in T2DM patients and show significant correlation with renal glomerular filtration rate (rGFR) [32]. Both clinical and preclinical data establish circulating FABP4 as an emerging biomarker for renal injury and a potential predictor of cardiovascular events in ESRD patients [33].

Fatty acid oxidation (FAO), or β-oxidation, is a mitochondrial oxygen-dependent process that progressively catabolizes fatty acids into acetyl-CoA through sequential enzymatic reactions, generating substantial metabolic energy. In the kidney, FAO serves as the primary mechanism for lipid clearance. However, impaired FAO has been strongly associated with DKD pathogenesis. A longitudinal study of American Indians with type 2 diabetes (n = 92) demonstrated significantly diminished renal FAO capacity [21]. This metabolic dysfunction correlates with downregulation of key FAO regulators and concomitant accumulation of intracellular lipids in both human and murine models exhibiting tubulointerstitial fibrosis [23]. The long-chain acyl-CoA synthetase 1 (ACSL1) plays a role in DKD progression, both as a modulator of saturated fatty acid-induced inflammatory responses and as a critical enzyme in β-oxidation [34]. Notably, ACSL1 overexpression induces lipid peroxidation, triggering ferroptosis—an iron-dependent form of programmed cell death [35]. Similarly, carnitine palmitoyltransferase 1A (CPT1A), the rate-limiting enzyme of FAO, mediates mitochondrial fatty acid import via carnitine conjugation. Renal tubular epithelial cells with inhibited CPT1A activity exhibit hallmark features of metabolic dysfunction, including ATP depletion and pathological lipid accumulation [36]. Peroxisome proliferator-activated receptors (PPARs) play a pivotal role in the regulation of renal FAO. As members of the type II nuclear hormone receptor superfamily, PPARs comprise three isoforms (PPARα, PPARβ/δ, and PPARγ) that differentially modulate lipid metabolism [37]. PPARα specifically enhances FAO and oxidative phosphorylation [38], while PPAR-α and PPAR-δ primarily regulate FAO-related gene expression, and PPARγ predominantly governs lipogenesis and lipid storage [39]. In DKD, murine models demonstrate that downregulation of both PPARα and PPARδ significantly impairs FAO capacity [40]. Conversely, PPARγ maintains renal metabolic homeostasis, with its inhibition leading to tubular hypertrophy, tubulointerstitial fibrosis, and renal dysfunction [41]. Furthermore, Lipin-1 acts as a crucial bifunctional regulator, functioning both as a phosphatidic acid phosphatase for triglyceride synthesis and as a transcriptional co-activator for lipid oxidation. In DKD, renal Lipin-1 expression progressively declines. Recent evidence demonstrates that Lipin-1 deficiency acts as a primary pathogenic driver in proximal tubular epithelial cells (PTECs) by triggering dual metabolic disruptions. Specifically, Lipin-1 deficiency inhibits the PGC-1α/PPARα-mediated Cpt1α/HNF4α signaling pathway, which substantially downregulates fatty acid oxidation (FAO) and induces mitochondrial dysfunction. Simultaneously, it upregulates sterol regulatory element-binding proteins (SREBPs), thereby actively promoting de novo lipogenesis. This detrimental combination of diminished lipid clearance and enhanced lipid synthesis causes massive ectopic lipid deposition in PTECs. Ultimately, this severe lipotoxicity exacerbates energy depletion and accelerates tubulointerstitial fibrosis in DKD [42].

Cholesterol metabolism

Cholesterol, the predominant sterol in mammalian systems, demonstrates particularly high concentrations in neural tissues and the brain. It also accumulates in visceral organs (kidneys, spleen, liver, and small intestinal mucosa) as well as in peripheral tissues including skin and adipose depots. Beyond its fundamental role as a structural component of cellular membranes, cholesterol critically modulates the physicochemical properties of membranes and the conformation of membrane proteins [43]. Furthermore, cholesterol is a precursor for the synthesis of bile acids and sterol hormones (adrenocorticotropic hormone, sex hormones, etc.) and plays an important role in embryonic development. Cholesterol metabolism can be divided into four main components: endogenous synthesis, exogenous uptake, exocytosis and esterification [43].

Cholesterol biosynthesis is a complex, energetically demanding metabolic pathway that converts acetyl-CoA into cholesterol through tightly coordinated enzymatic reactions. This pathway serves as the cornerstone of cellular cholesterol homeostasis, governed by two central regulators: (1) sterol regulatory element-binding protein 2 (SREBP2), the master transcriptional controller of cholesterogenic genes, and (2) hydroxymethylglutaryl-CoA (HMG-CoA) reductase, the rate-limiting enzyme that catalyzes the conversion of HMG-CoA to mevalonate – the committed step in cholesterol synthesis. Clinical evidence from the Nephroseq database reveals significant upregulation of both SREBP1 and SREBP2 in glomeruli of DKD patients [44], [45]. Experimental models demonstrate parallel dysregulation in diabetic rats, showing renal accumulation of lipid droplets alongside increased expression of HMG-CoA reductase, low-density lipoprotein receptor (LDLR), SREBP2, and SREBP-cleavage activating protein (SCAP) [46]. The activation mechanism of SREBP2 involves its SCAP-mediated translocation from the endoplasmic reticulum (ER) to the Golgi apparatus, a process inhibited by insulin-induced gene (INSIG) protein when cellular cholesterol levels are sufficient [43]. Further evidence from diabetic mouse models shows aberrant expression of adipocyte differentiation-related proteins and dysregulated HMG-CoA reductase activity, correlating with renal lipid droplet deposition [47]. The therapeutic relevance of modulating this pathway is exemplified by simvastatin, an HMG-CoA reductase inhibitor, which lowers LDL-cholesterol (LDL-C) and has been reported to ameliorate diabetic proteinuria and attenuate estimated glomerular filtration rate (eGFR) decline, possibly by suppressing lipid peroxidation and apoptosis [48], [49].

Cholesterol transport in circulation is principally mediated by two lipoprotein classes: low-density lipoprotein (LDL) and high-density lipoprotein (HDL). Cellular cholesterol influx occurs predominantly through LDL receptor (LDLR)-mediated endocytosis, where this plasma membrane glycoprotein facilitates LDL-cholesterol uptake from circulation. In DKD, hyperglycemia disrupts normal LDLR feedback regulation in podocytes, leading to pathological intracellular lipid accumulation and maladaptive phenotypic changes that accelerate disease progression [50], [51]. Research has shown that streptozotocin (STZ)-induced diabetic atherosclerosis in LDL receptor-deficient (LDLR^-/-) mice can result in renal injury [52]. The interplay between inflammation and cholesterol metabolism is particularly significant, as proinflammatory cytokines impair cholesterol-mediated LDLR regulation in mesangial cells. This dysregulation permits uncontrolled accumulation of unmodified LDL and subsequent foam cell formation – a hallmark of lipid-mediated renal damage [53]. Clinical observations corroborate these findings, showing marked upregulation of cholesterol uptake receptors (including LDLR, oxidized LDLR, and acetylated LDLR) in renal biopsies from DKD patients [9].

As the master transcriptional regulators of cellular cholesterol homeostasis, liver X receptors (LXRs), particularly LXR-α, act as critical upstream sensors that prevent intracellular lipid toxicity. Upon sensing excess intracellular cholesterol derivatives (such as oxysterols), LXR-α is activated, forms a heterodimer with the retinoid X receptor (RXR), and binds to LXR response elements (LXREs) on target genes. The primary metabolic function of LXR-α is to drive the transcription of cholesterol efflux transporters, prominently ABCA1 and ABCG1, thereby facilitating reverse cholesterol transport. Beyond lipid clearance, LXR-α serves as a vital molecular link between lipid metabolism and renal inflammation. Preclinical evidence demonstrates that LXR activation preserves glomerular integrity by broadly suppressing pro-inflammatory pathways, including the downregulation of osteopontin and the alleviation of inflammatory responses in mesangial cells [54], [55]. Furthermore, LXR agonism exerts protective effects on the glomerular endothelium by upregulating thrombomodulin, thereby attenuating inflammation and thrombosis-associated renal injury [56]. Conversely, LXR deficiency has been shown to accelerate intraglomerular cholesterol accumulation and exacerbate renal decline in diabetic models, highlighting the indispensable role of LXR-α in mitigating lipotoxicity-driven diabetic kidney disease [57].

Cholesterol efflux serves as a critical regulatory mechanism for maintaining cellular cholesterol homeostasis by preventing intracellular cholesterol overload. This process mediates the removal of excess cholesterol through two primary routes: transport to extracellular acceptors for reverse cholesterol transport, and sequestration into intracellular lipid droplets for storage. In most tissues, excess cholesterol is exported to the bloodstream or bile through members of the ATP-binding cassette (ABC) transporter family, including ABCA1 and ABCG1, where it either contributes to high-density lipoprotein (HDL) formation or undergoes bodily excretion. Diabetic mice, especially those developing nephropathy, demonstrate significant intrarenal lipid accumulation concomitant with markedly reduced renal expression of cholesterol transporters ABCA1, ABCG1, and scavenger receptor class B type I (SR-BI) [58]. Clinical and preclinical evidence consistently shows that ABCA1 downregulation correlates with DKD progression markers, as observed in both human patients and diabetic mouse models (BTBR ob/ob and db/db strains) [59], [60]. ABCA1 deficiency in glomerular endothelial cells exacerbates renal pathology in type 2 diabetic mice, manifested through: elevated serum creatinine, worsened proteinuria, mesangial matrix expansion, podocyte foot process effacement, enhanced renal inflammation and cellular apoptosis [10]. In vitro studies reveal that human podocytes exposed to serum from type 1/type 2 diabetes patients (including early-stage DKD) develop increased lipid droplet accumulation and reduced ABCA1 expression [59], [61]. Mechanistically, impaired ABCA1-mediated cholesterol efflux in both macrophages and renal tissue contributes to diabetic complications by promoting systemic atherosclerosis and accelerating nephropathy progression through sustained cellular cholesterol overload [62]. Emerging evidence identifies CCDC92 as a novel modulator of lipid homeostasis that exacerbates renal injury through post-translational regulation of ABCA1. Mechanistically, CCDC92 promotes ABCA1 degradation by enhancing PA28α-dependent proteasomal activity, ultimately impairing cholesterol efflux capacity and increasing susceptibility to podocyte injury and glomerular damage [7], [63]. LXR-α rs7120118 was found to be significantly associated with an elevated risk of DKD, while ABCA1 rs2230806 was significantly associated with an elevated risk of DKD in Chinese Han individuals without hypercholesterolemia [64].

Sphingolipid metabolism

Sphingolipids comprise a diverse class of lipids characterized by a sphingoid long-chain base backbone. Emerging research has established these molecules and their metabolites as critical signaling mediators involved in the pathogenesis of various diseases. Among the most extensively studied metabolites are ceramide (CER), CER-1-phosphate (C1P), and sphingosine-1-phosphate (S1P), which have been shown to either promote or suppress apoptosis, autophagy, inflammation, immunity, and membrane fluidity [65].

Patients with DKD have elevated levels of long-chain ceramides (C16:0, C18:0, and C20:0) and ultra-long-chain ceramides (C22:0, C24:0) [66], [67]. Ceramide is a biologically active sphingolipid that is a substrate for the production of C1P and S1P [68]. Preclinical studies demonstrate that genetic or pharmacological reduction of ceramides improves renal function and attenuates histopathological damage in rodent models. In parallel, clinical studies have shown that DKD patients exhibit distinct circulating sphingolipid profiles compared with diabetic controls, characterized in part by increased levels of long-chain and ultra-long-chain ceramide species [69]. Notably, ceramide synthase 6 (CerS6), highly expressed in podocytes, drives proteinuria when overexpressed [70], and mitochondrial ceramide accumulation—induced by high-fat diets in OLETF rats—an established model of obese type 2 diabetes—and in mice exacerbates podocyte injury via reactive oxygen species [71]. Upregulation of serine palmitoyltransferase, a key enzyme involved in the ab initio synthesis of ceramide, led to increased ceramide production, which was associated with STZ-induced increased apoptosis of renal tubular epithelial cells and microvascular endothelial cells in DKD [72]. Elevated plasma S1P levels have been consistently observed in both type 1 [73] and type 2 diabetic rodent models [74], with similar increases reported in renal tissue of streptozotocin-induced diabetic mice [75]. Of the five known S1P receptors (S1PR1-S1PR5), S1PR1-S1PR4 are functionally expressed in the kidney, where S1PR1 activation has been shown to exert renoprotective effects in DKD rat models [76]. Sphingomyelin phosphodiesterase acid-like 3b (SMPDL 3b) is a lipid raft sphingomyelinase that alters plasma lipid composition, modulates intracellular inflammatory pathways, and controls the ability of circulating factors to affect podocyte function and survival [77]. Mechanistically, SMPDL3b controls membrane fluidity by inhibiting ceramide kinase translocation, thereby limiting the conversion of ceramide to ceramide-1-phosphate (C1P). An excess of SMPDL3b has been demonstrated to affect the production of active sphingolipids, resulting in a reduction in C1P content. This phenomenon has been observed in human podocytes in vitro and in the renal cortex of diabetic db/db mice in vivo. In DKD, excess SMPDL3b is more likely to be pathogenic than protective. By inhibiting ceramide kinase translocation, SMPDL3b reduces the conversion of ceramide to ceramide-1-phosphate (C1P), thereby shifting sphingolipid balance toward ceramide accumulation and C1P depletion [78]. In podocytes, this change is expected to aggravate lipotoxic stress by impairing membrane lipid organization and insulin receptor signaling, while promoting oxidative stress, cytoskeletal instability, apoptosis, and ultimately albuminuria [79].

The gut-liver-renal axis in lipid dysregulation

Emerging evidence highlights the gut-liver-renal axis as a crucial systemic driver of lipid metabolic abnormalities in DKD [80]. In the context of diabetes, gut microbiome dysbiosis alters the production of key microbial metabolites, including short-chain fatty acids (SCFAs), bile acids, and trimethylamine N-oxide (TMAO) [81], [82]. These gut-derived signals strictly modulate the liver, which serves as the central hub of lipid homeostasis. The altered intestinal permeability and aberrant gut signaling, coupled with hepatic insulin resistance, exacerbate the hepatic overproduction of triglyceride-rich lipoproteins and disrupt cholesterol clearance [83]. Consequently, these systemic lipid perturbations lead to elevated circulating lipotoxic species that are delivered to the kidneys. The continuous influx of these abnormal circulating lipids ultimately overwhelms renal lipid clearance pathways, accelerating ectopic lipid deposition, oxidative stress, and inflammatory responses in renal cells80, [84]. Furthermore, systemic interventions targeting this axis—such as modifying gut microbiota to restore bile acid and glycerophospholipid metabolism—have shown potential in mitigating renal lipotoxicity, further underscoring the indispensable role of the gut-liver-renal crosstalk in DKD pathogenesis [85].

The impact of aberrant lipid metabolism in DKD on renal cells

Podocytes

Podocytes, the specialized epithelial cells critical for maintaining the glomerular filtration barrier, are particularly vulnerable to lipotoxicity in DKD. Podocyte apoptosis, driven by lipid accumulation and metabolic dysregulation, is a key contributor to the progression of diabetic nephropathy, leading to glomerular basement membrane denudation, albuminuria, and eventual glomerulosclerosis [86], [87]. Lipotoxicity and lipid accumulation can cause damage and apoptosis in podocytes in patients with DKD, and podocytopenia is an independent predictor of DKD progression [88]. In DKD, podocytes exhibit excessive uptake of cholesterol esters (ChE) and FAs, which disrupts cellular homeostasis and promotes lipotoxic injury [86]. Saturated fatty acids exacerbate podocyte damage by inducing endoplasmic reticulum (ER) stress, apoptosis, and necrosis [89], [90], while impaired FAO and increased CD36-mediated FFA uptake further exacerbate intracellular lipid accumulation and oxidative stress, accelerating podocyte dysfunction in early-stage nephropathy [91]. FFAs bind to G-protein-coupled receptors (GPCRs; e.g., FFAR1-3), activating the Gβ/Gγ complex and RAC1, disrupting the podocyte cytoskeleton [92]. Pharmacological intervention with the dual GPR40/GPR84 antagonist PBI-4050 mitigates podocyte loss in diabetic eNOS^-/- db/db mice [93], while sterol-O-acyltransferase-1(SOAT1) inhibition reduces lipotoxicity by enhancing ABCA1-mediated cholesterol efflux [94]. Additionally, morroniside improves podocyte lipid metabolism by modulating the PGC-1α/LXR/ABCA1 (cholesterol efflux) and PGC-1α/PPARγ/CD36 (lipid uptake) pathways [95]. Lipid-driven inflammation in podocytes triggers epithelial-mesenchymal transition (EMT) and upregulates the LDLR/SCAP/SREBP2 axis, promoting ER-to-Golgi translocation of the SCAP/SREBP2 complex and further exacerbating lipid accumulation [96]. Impaired reverse cholesterol transport is a hallmark of DKD, though cyclodextrin therapy shows promise in restoring podocyte function by enhancing reverse cholesterol transport [60]. Furthermore, VEGF-B inhibition improves insulin sensitivity and reduces nephrolipotoxicity in DKD mice [97], while podocyte-specific deletion of junctional adhesion molecule-like protein (JAML) attenuates proteinuria and podocyte injury [98]. Notably, sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b), upregulated in DKD glomeruli and serum-treated podocytes, exacerbates apoptosis via interaction with soluble urokinase plasminogen activator receptor (suPAR) [99]. Oxidized LDL (ox-LDL) deposition further damages podocytes, an effect counteracted by Klotho through IGF-1R/RAC1/OLR1 signaling [100]. Collectively, these findings underscore the central role of lipid metabolic dysregulation in podocyte injury and highlight potential therapeutic targets for DKD (Fig. 2).

Fig. 2.

Pathogenic mechanisms of lipotoxicity across distinct renal cell populations in diabetic kidney disease (DKD). Under the synergistic influence of circulating lipotoxic species, sphingolipids, and high glucose, aberrant lipid metabolism triggers specific intracellular cascades in four major renal cell types. (Top left) In podocytes, excessive uptake of free fatty acids (FFAs) via CD36 and GPCRs induces endoplasmic reticulum (ER) stress and cytoskeletal disruption, ultimately leading to foot process effacement and SMPDL3b-driven apoptosis. (Top right) In renal tubular epithelial cells, receptors such as FATP2 and KIM-1 facilitate the pathological influx of albumin-bound FFAs. This lipid overload impairs fatty acid oxidation (FAO) in damaged mitochondria and promotes massive lipid droplet accumulation mediated by SREBP1 and ADRP, culminating in lipoapoptosis. (Bottom left) Mesangial cells exhibit uncontrolled LDL uptake via dysregulated LDL receptors (LDLR), transforming into lipid-laden foam cells. This intracellular lipid accumulation triggers a phenotypic switch toward a pro-fibrotic phenotype, resulting in the pathological expansion of the extracellular matrix. (Bottom right) In glomerular endothelial cells, the downregulation of LXR and ABCA1 significantly impairs cholesterol efflux, leading to intracellular cholesterol crystal accumulation. This exacerbates oxidative stress (ROS) and triggers pore formation, ultimately resulting in endothelial pyroptosis. The adjacent cross-sections illustrate progressive wall thickening and luminal narrowing in arterioles.

Renal tubular epithelial cells

Renal tubular epithelial cells, particularly proximal tubule cells with their high energy demands and reliance on FAO, are highly susceptible to lipotoxicity in DKD. Patients with DKD and db/db mice exhibit impaired lipophagy, ectopic lipid deposition, and increased lipotoxic injury in tubular cells [101], [102]. Key regulators of tubular lipid accumulation include adipose differentiation-related protein (ADRP) and sterol regulatory element-binding protein 1 (SREBP1), which drive lipid droplet formation and inflammation, positioning ectopic lipid accumulation as a potential therapeutic target [102]. Mitochondrial oxidative damage can lead to renal tubular epithelial cell injury and lipid peroxidation induced by lipid accumulation [103]. Mitochondrial dysfunction exacerbates tubular injury, as impaired FAO - the primary energy-generating pathway in tubular cells-leads to ATP depletion, cell death, dedifferentiation, and intracellular lipid deposition [23]. Hyperglycemia further disrupts lipid homeostasis by upregulating SREBP-1c and SREBP2, along with their downstream targets (e.g., fatty acid synthase [FASN], HMG-CoA reductase), promoting lipid accumulation in tubular cells [104]. While albumin alone is non-toxic, FFAs bound to albumin induce proximal tubular mesenchymal injury [105], mediated in part by fatty acid transport protein 2 (FATP2), a major apical FFA transporter that regulates apoptosis [106]. Kidney injury molecule-1 (KIM-1), expressed on proximal tubular membranes, recognizes phosphatidylserine on apoptotic cells and oxidized lipoproteins, exacerbating tubular damage [107]. In T2DM, persistent hyperglycemia and insulin resistance increase circulating FFAs, oxidative stress, and albuminuria, thereby enhancing the exposure of proximal tubular cells to albumin-bound lipids. Hyperglycemia also activates ROS-, PKC-, and SREBP-dependent signaling pathways that favor lipid uptake and suppress lipid efflux, predisposing tubular cells to lipotoxic injury. KIM-1 also facilitates the uptake of palmitic acid (PA)-bound albumin, triggering DNA damage, cell cycle arrest, interstitial inflammation, fibrosis, and secondary glomerulosclerosis [108]. Additionally, acyl-CoA synthetase long-chain family member 5 (ACSL5) mediates lipoapoptosis in diabetic proximal tubules [109], while phosphofurin acidic cluster sorting protein 2 (PACS-2) deficiency disrupts lipid synthesis, uptake, and cholesterol efflux, worsening tubular lipid accumulation in DKD [110]. Cholesterol efflux in tubular cells is regulated by ABCA1, ABCG1, and scavenger receptor class B type I (SR-BI), which mediate cholesterol transfer to apolipoprotein A1 (ApoA1) and high-density lipoprotein (HDL) [58]. Disulfide-bond A oxidoreductase-like protein (DsbA-L), a glutathione S-transferase family member with roles in lipid metabolism, is highly expressed in proximal tubules and may modulate renal lipotoxicity [111], [112]. Finally, Annexin A1 (ANXA1) deficiency exacerbates renal injury in high-fat diet/streptozotocin-induced diabetic mice, correlating with tubulointerstitial lipid deposition in human DKD kidneys [113].

Mesangial cell

Mesangial cells, specialized glomerular pericytes that maintain capillary structure and hemodynamics [114], undergo pathogenic expansion in T2DM and obesity-related renal injury, driving early glomerulosclerosis in DKD [19], [115]. Ectopic lipid accumulation in these cells-alongside podocytes and tubular cells-reflects a maladaptive response to hyperfiltration and albuminuria, hallmark features of obesity-associated glomerulopathy (ORG) [116]. Mesangial cells express LDL receptors and CD36/fatty acid translocase (FAT), but inflammatory cytokines disrupt cholesterol-mediated feedback regulation, leading to uncontrolled uptake of unmodified LDL and foam cell formation [53], [116], [117]. Insulin-like growth factor-1 (IGF-1) is linked to diabetes through the altered metabolic and growth-factor signaling environment of the diabetic kidney. Under hyperglycemic and dyslipidemic conditions, IGF-1 promotes mesangial lipid accumulation and dysfunction, thereby contributing to the pathogenesis of DKD. It exacerbates lipid accumulation, impairing contractile and migratory responses critical for glomerular function [118]. Intracellular LDL accumulation triggers phenotypic switching, with lipid-laden mesangial cells losing contractility and adopting a pro-fibrotic phenotype [53]. This process mirrors atherogenesis, where oxidized lipids and inflammation drive foam cell formation. These findings highlight mesangial lipid metabolism as a potential therapeutic target, with interventions aimed at modulating lipid uptake receptors or inflammatory signaling pathways offering promising avenues for preserving glomerular function in diabetes.

Glomerular endothelial cells and arterioles

Glomerular endothelial cells (GECs) and their associated afferent and efferent arterioles are critical vascular components highly susceptible to lipotoxicity in DKD. Concurrent hyperglycemia and dyslipidemia synergistically exacerbate intracellular cholesterol accumulation in GECs by downregulating LXRs and ABCA1 [119]. This impairs cholesterol efflux, induces oxidative stress, and triggers endothelial pyroptosis [120]. Beyond the capillary tuft, aberrant lipid metabolism accelerates hyaline arteriolosclerosis in both afferent and efferent arterioles. The subendothelial exudation of circulating lipids and plasma proteins leads to arteriolar wall thickening, luminal narrowing, and impaired myogenic autoregulation. Consequently, this structural remodeling disrupts glomerular hemodynamics, driving early-stage hyperfiltration and mechanical stretch injury [121]. Concurrently, lipotoxic GECs exhibit disrupted VEGF-NO signaling, which secondarily exacerbates podocyte apoptosis through pathogenic intercellular crosstalk [122]. Collectively, targeting endothelial and arteriolar lipid homeostasis represents an indispensable strategy for halting DKD progression.

Targeting lipid metabolism for the treatment of DKD

Emerging therapies targeting lipid metabolism show considerable promise for DKD management. SGLT2 inhibitors have demonstrated consistent renoprotective effects across multiple studies, with a systematic review confirming their efficacy in slowing progression to end-stage renal disease in type 2 diabetic nephropathy [123]. Specifically, canagliflozin has shown multifaceted benefits in diabetic mice, including improved renal function, reduced lipid droplet accumulation, upregulated CPT1A expression (the rate-limiting enzyme of fatty acid oxidation), enhanced FAO capacity, and protection against ferroptosis [124]. Lipidomic analyses further reveal that canagliflozin promotes lipolysis and reduces tubular lipid deposition [125]. Clinical evidence supports these findings, with empagliflozin demonstrating reduced renal fat accumulation and advanced glycation end-products compared to metformin alone in diabetic patients [126].

Beyond SGLT2 inhibitors, GLP-1 receptor agonists like liraglutide exhibit renoprotective effects by modulating lipid metabolism. In DKD models, liraglutide reduces ectopic lipid deposition through dual mechanisms: inhibition of SREBP-1/FAS-mediated lipogenesis and activation of ATGL/HSL(adipose triglyceride lipase/hormone-sensitive lipase)-driven lipolysis, effectively countering palmitic acid-induced lipid accumulation in tubular cells [127].

Statins, while remaining first-line lipid-lowering agents, present a complex profile in DKD. Although they protect podocytes from oxidized LDL-induced apoptosis in vitro [128], long-term use may paradoxically increase renal lipid uptake and inhibit FAO in diabetic mice, potentially exacerbating DKD progression [129]. Clinical data show statins reduce proteinuria and mortality but may not slow non-end-stage CKD progression [130], highlighting the need for further investigation into their risk–benefit ratio in DKD.

Recently, Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i), such as alirocumab and evolocumab, have emerged as a novel therapeutic class with promising renoprotective potential against dyslipidemia-induced damage in DKD. Beyond its classical role in promoting the lysosomal degradation of hepatic low-density lipoprotein receptors (LDLR), PCSK9 is heavily implicated in renal lipotoxicity and inflammation. Mechanistically, PCSK9 exacerbates diabetic nephropathy by directly activating the cGAS/STING inflammatory pathway [131] and inducing the downregulation of the megalin receptor in the proximal tubule, which impairs protein reabsorption and aggravates proteinuria [132]. Experimental models have demonstrated that PCSK9 inhibition effectively rescues megalin levels, downregulates lipid-related proteins (e.g., Angptl3), and inhibits TGF-β signaling, thereby ameliorating renal lipid metabolism and reducing proteinuria [[132], [133]]. Clinically, unlike statins—which may paradoxically upregulate circulating PCSK9 levels—PCSK9i provide safe and profound LDL-C reduction in patients with mild-to-moderate CKD without worsening renal function or increasing the risk of new-onset diabetes [[134], [135]]. While current evidence strongly supports their efficacy in lowering cardiovascular risks in CKD patients, large-scale randomized controlled trials are warranted to fully elucidate the long-term renoprotective benefits of PCSK9i in DKD.

PPAR agonists represent another promising avenue. Fenofibrate (PPARα agonist) reduces glomerular oxidative stress and lipid accumulation in high-fat diet models, preventing albuminuria and fibrosis [136]. Pioglitazone, a PPARγ agonist, has also been reported to downregulate renal Twist-1 expression and preserve renal function in Zucker diabetic fatty rats, supporting its renoprotective potential in DKD-related metabolic injury [137]. Notably, dual PPARα/γ agonists like tesaglitazar demonstrate comprehensive metabolic benefits – improving insulin sensitivity, glycemic control, and dyslipidemia while significantly reducing albuminuria and glomerular fibrosis in db/db mice [138]. These findings position dual PPAR agonists as a potentially transformative approach for addressing both metabolic dysfunction and nephrolipotoxicity in DKD.

Emerging evidence highlights the therapeutic potential of herbal compounds in addressing lipid metabolism disorders associated with DKD. Astragaloside IV (AS-IV), a key bioactive component of Astragalus membranaceus, significantly reduces renal lipid deposition by modulating heme oxygenase-1 (HMOX1)-mediated lipid metabolism, thereby delaying DKD progression [139]. Baicalin demonstrates dual benefits by upregulating CPT1α-mediated fatty acid oxidation [140] while targeting FKBP51 to improve lipid homeostasis [141], resulting in notable anti-fibrotic effects. Berberine corrects glucose-lipid metabolic imbalances and protects podocytes by inhibiting Drp1-mediated mitochondrial dysfunction, ultimately reducing glomerulosclerosis and albuminuria in diabetic models [142]. The diterpene compound Lei Gong Teng Lactone, derived from Tripterygium wilfordii, ameliorates albuminuria and nephropathy in obese and dyslipidemic db/db mice [143]. Resveratrol exerts renoprotective effects through modulation of the SREBP-1/ChREBP axis in the JAML/Sirt pathway and activation of AMPK/SIRT1-PGC-1α signaling, reducing renal lipid deposition, oxidative stress, and apoptosis [16], [144]. Yishen Huashi Granule acts via the gut-kidney axis, with glycerophospholipid metabolism emerging as a key mechanistic target among its six identified lipid-glucose regulatory pathways [85]. See Table 1 for the above information.

Table 1.

Therapeutic agents targeting lipid metabolism in diabetic kidney disease.

Agent/therapeutic strategy	Experimental model	Target/mechanism of action	References
SGLT2 inhibitors
Canagliflozin	db/db mice; HG-induced HK2 cells	Upregulates FOXA1-CPT1A expression, enhances fatty acid oxidation, reduces tubular lipid deposition, and inhibits ferroptosis.	[124]
Dapagliflozin	DKD patients; STZ-induced SD rats; db/db mice; PA-stimulated BV2 microglia	Upregulates MCPIP1, ameliorates central neuroinflammation, and modulates tubular lipid metabolism.	[125]
Empagliflozin	T2DM patients; db/db mice raised with the basal diet or the high-AGEs diet; HK-2 cells	Inhibited the AGEs-RAGE pathway, alleviating diabetic renal tubular cholesterol accumulation.	[126]
GLP-1 receptor agonists
Liraglutide	Male SD rats treated with high-fat diet + unilateral nephrectomy + low-dose STZ	Inhibits SREBP-1/FAS-mediated lipogenesis, activates ATGL/HSL-driven lipolysis, and reduces tubular lipid accumulation.	[127]
Statins
Simvastatin	Male STZ-induced Wistar rats	Inhibits HMG-CoA reductase, suppresses lipid peroxidation and apoptosis.	[49]
PCSK9 Inhibitors
Alirocumab/Evolocumab/PCSK9 mAb	Podocin knockout mice; Cultured proximal tubule cells	Rescues megalin receptor levels, prevents its lysosomal degradation, and decreases urinary albumin excretion.	[132]
	HFD/STZ-induced diabetic mice; HGPA-induced HK-2 cells	Inhibits cGAS/STING pathway activation, reduces mitochondrial DNA damage, and alleviates renal inflammation.	[131]
	Patients with CKD (Systematic reviews of clinical trials)	Provides profound LDL-C reduction without worsening renal function or increasing the risk of new-onset diabetes.	[134], [135]
PPAR agonists
Fenofibrate (PPARα agonist)	Male C57BL/6 mice treated with low-fat diet and high-fat diet	Enhances renal lipolysis, reduces glomerular oxidative stress and lipid accumulation, and improves proteinuria and fibrosis.	[136]
Tesaglitazar (PPARα/γ dual agonist)	db/db mice	Improves insulin sensitivity, glycemic control, and dyslipidemia while reducing albuminuria and glomerular fibrosis.	[138]
Pioglitazone (PPARγ agonist)	Male Zucker diabetic fatty (ZDF) rats	Downregulate Twist-1 expression in the kidney.	[137]
Herbal compounds
Astragaloside IV (AS-IV)	C57BL/6 mice treated with HFD combined with low-dose STZ	Modulates HMOX1-mediated lipid metabolism and reduces renal lipid deposition.	[139]
Baicalin	db/db mice; HG-induced HK2 cells; DKD patients	Upregulates CPT1α-mediated FAO, diminishes renal fibrosis	[140]
	High-fat-diet/STZ-induced DKD mouse	Targets FKBP51 to improve lipid homeostasis.	[141]
Berberine	db/db mice and mouse podocytes	Inhibits Drp1-mediated mitochondrial fission, protects podocytes, and reduces glomerulosclerosis and albuminuria.	[142]
Triptolide	db/db mice	Ameliorates albuminuria and nephropathy in obese diabetic db/db mice.	[143]
Resveratrol	DKD patients; C57BL/6 mice treated with HFD	Regulates the JAML/Sirt1 lipid synthesis pathway	[16]
	db/db mice	Modulates AMPK/SIRT1-PGC-1α pathway to reduce renal lipid deposition and oxidative stress.	[144]
Yishen Huashi Granule	STZ-induced rats	Regulates glycerophospholipid metabolism via the “gut-kidney axis.”

Conclusion

The term lipotoxicity is used to describe the ectopic accumulation of lipids in non-adipose tissues and organs. This phenomenon is closely associated with dysfunctional signalling in non-adipose tissues, including the myocardium, pancreas, skeletal muscle, liver and kidneys. It is also linked to the development of insulin resistance. There is a strong correlation between the development of diabetic nephropathy, a common complication of diabetes mellitus, and disorders of lipid metabolism. The prevalence of these disorders in patients with DKD, and their appearance early in the disease, indicate a significant link between the two. A number of studies have demonstrated that abnormalities in fatty acid uptake and oxidation, impairment of cholesterol metabolism, increased lipid uptake or synthesis, and imbalance of biologically active sphingolipids all contribute to the progression of DKD. Disturbances in lipid metabolism may result in damage to multiple cell types within the kidney, including podocytes, tubular epithelial cells, and thylakoid cells. This may subsequently lead to glomerulosclerosis and renal failure. Therefore, the early identification and intervention of lipid metabolism disorders is of critical importance in preventing the onset and progression of DKD. The improvement of disorders of lipid metabolism provides new targets for the development of therapeutic strategies in DKD.

Potential renal protective benefits beyond conventional glucose-lowering therapies may be achieved through strategies such as: enhancing fatty acid oxidation, modulating cholesterol efflux via ABCA1/ABCG1 or inhibiting pathogenic sphingolipid accumulation. However, the long-term efficacy and safety of these interventions require further validation in large-scale clinical trials. Future studies should delineate cell-specific lipid metabolic alterations to identify precise therapeutic targets. Circulating and urinary lipid species require rigorous validation as early predictive biomarkers for DKD progression. Investigating synergistic mechanisms between lipid-modifying agents and conventional antidiabetic drugs may reveal novel strategies to mitigate renal lipotoxicity. Addressing these knowledge gaps will not only advance our mechanistic understanding of DKD pathogenesis but also facilitate the development of personalized interventions tailored to individual metabolic profiles.

CRediT authorship contribution statement

You Wang: Writing – review & editing, Writing – original draft, Methodology. Lijia Wu: Writing – review & editing. Xincui Bao: Writing – review & editing. Jing Yang: Writing – review & editing. Miao Xu: Writing – review & editing. Yuzhuo Chang: Writing – review & editing. Zhe Liu: Writing – review & editing. Lingling Qin: Writing – review & editing. Ming Gao: Writing – review & editing. Cuiyan Lv: Writing – review & editing, Methodology. Tonghua Liu: Supervision, Funding acquisition.

Funding

This work was supported by the Traditional South African Herbal Medicine for the Treatment of Diabetes (2021YFE0106300).

Declaration of competing interest

The authors declare no conflicts of interest.