AMP-activated protein kinase (AMPK) serves as a cellular energy sensor activated during energy deficit to coordinate metabolic adaptations and maintain energy homeostasis. AMPK-mediated lipophagy promotion primarily occurs through suppression of downstream mechanistic target of rapamycin (mTOR) signaling (Chauhan et al., 2023). Under diabetic environment, AMPK activation enhances cellular fatty acid β-oxidation and stimulates autophagic clearance of lipids within renal tubular cells (Chauhan et al., 2023). Futhermore, mTOR acts as a pivotal signaling integrator that modulates cellular growth and metabolism in response to nutrient availability and growth factors (Goul et al., 2023; Shi et al., 2024). Upon AMPK activation, phosphorylation of downstream mTOR effectors suppresses mTOR activity, thereby inducing autophagy and enhancing cellular adaptation to energy stress (Oza et al., 2021). Importantly, mTOR hyperactivation potently inhibits autophagy, exacerbating intracellular lipid accumulation and renal cellular dysfunction (Oza et al., 2021). Collectively, AMPK/mTOR signaling represents a core regulatory axis for lipophagy modulation in DKD.

Peroxisome proliferator-activated receptors (PPARs), including isoforms PPARα, PPARβ/δ, and PPARγ, comprise ligand-activated nuclear transcription factors critically regulating lipid metabolism, inflammatory responses, and energy homeostasis (Chen et al., 2024). PPARα and PPARγ agonists demonstrate significant lipophagy-modulating capacities. Substantial evidence confirmed natural medicines ameliorate metabolic syndrome-related pathologies, including DKD and lipid dysregulation, via PPAR signaling modulation (Zou et al., 2023). Specifically, natural medicines such as resveratrol and genistein activate PPARα, subsequently enhancing fatty acid catabolism and mitigating ectopic lipid accumulation (Sharma et al., 2024). PPARγ agonists, including thiazolidinediones, clinically manage type 2 diabetes by improving insulin sensitivity, promoting adipocyte differentiation, and inhibiting adipocyte apoptosis (Ma et al., 2021; Sharma and Patial, 2022). These findings collectively underscore the centrality of PPAR signaling in lipid-metabolism regulation and highlight the effectiveness of natural medicines in improving lipid-metabolism disorders in DKD via PPAR-pathway activation.

Sirtuin 1 (SIRT1), an NAD⁺-dependent deacetylase, orchestrates critical cellular processes including autophagy, metabolic regulation, and senescence. SIRT1 activates autophagic machinery through deacetylation, thereby enhancing intracellular lipid clearance. Mechanistically, SIRT1 activation deacetylates forkhead box protein O1 (FoxO1), augmenting FoxO1-mediated autophagic processes that promote lipid elimination (Wang et al., 2015; Xu M. et al., 2024). FoxO1, acting as a transcription factor, modulates expression of lipophagy-related genes such as adipose triglyceride lipase (ATGL), whose activation accelerates fatty acid oxidation and lipid hydrolysis (Chakrabarti et al., 2011; Zhang et al., 2016). Moreover, SIRT1 activation promotes autophagy via the AMPK signalling pathway, and its interaction with FoxO1 becomes particularly critical under diabetic conditions (Chang et al., 2015; Xu Y. et al., 2024). Therefore, pharmacologically enhancing SIRT1 activity to promote FoxO1 deacetylation may therapeutically ameliorate renal lipid dysmetabolism in DKD, offering novel biological targets and therapeutic rationale.

Polyphenols abundant in traditional medicinal and dietary plants orchestrate lipophagy chiefly via activation of central signaling cascades including AMPK, SIRT1 and transcription factor EB (TFEB) (Giulia et al., 2020; Zhenyu et al., 2023). Resveratrol, a non-flavonoid polyphenol derived from many dietary plants, ameliorates renal lipid accumulation by deacetylating FoxO3, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), and Beclin1 (Claudia et al., 2022). In DKD models, Resveratrol significantly mitigates lipid accumulation and insulin resistance in DKD by activating autophagy via the AMPKα/mTOR pathway (Yong-Qi and Youjia, 2020). Specifically, it enhances phosphorylation of AMPKα, which inhibits mTOR activity and promotes autophagy activating kinase 1 (ULK1) activation. This cascade upregulates autophagy-related proteins Beclin1 and LC3 II/I, leading to the degradation of lipid droplets and improvement in renal lipid metabolism (Yong-Qi and Youjia, 2020). Beyond resveratrol, other polyphenolic metabolites exhibit nephroprotective efficacy. Ai et al. demonstrated that paeonol ameliorates DKD by activating TFEB-mediated lipophagy (Ai et al., 2025). Paeonol directly binds to RHEB, acting as an mTOR inhibitor, which promotes TFEB dephosphorylation and nuclear translocation. This activates the transcription of lysosomal genes lysosomal-associated membrane protein-2 (LAMP2), ATPase H + transporting V1 subunit A (ATP6V1A), and PGC-1α, enhancing lysosome biogenesis and restoring autophagic flux, ultimately leading to the clearance of excess renal tubular lipids and improved renal function (Ai et al., 2025).

Commonly isolated from traditional medicinal plants, terpenoids exhibit significant effects on renal lipophagy. Celastrol, isolated from the botanical drug Tripterygium wilfordii Hook. f (Celastraceae), ameliorates DKD by activating renal lipophagy through PI3K/AKT/mTOR pathway inhibition. In high-fat/high-glucose-diet and STZ-induced diabetic rats, celastrol significantly downregulated PI3K, p-AKT, and mTOR expression, leading to increased LC3-II levels, thereby attenuating podocyte injury, glomerular basement membrane thickening, and proteinuria (Nie et al., 2020). In addition, celastrol exerts pronounced renal lipophagy-regulatory efficacy by inducing lipophagy in clear cell renal cell carcinoma via liver X receptor α (LXRα)/ATP-binding cassette transporter A1 (ABCA1) pathway activation (Chan-juan et al., 2020). Celastrol activates LXRα to transcriptionally upregulate ABCA1, which is essential for cholesterol efflux and autophagic degradation of lipid droplets. Concurrently, celastrol induces canonical autophagy by inhibiting mTOR activity, enhancing LC3-I-to-LC3-II conversion, and degrading p62, thereby promoting lipid droplet sequestration and lysosomal breakdown (Chan-juan et al., 2020). By alleviating this lipid-rich environment, celastrol inhibits the epithelial-mesenchymal transition process, ultimately suppressing cancer cell proliferation, migration, invasion, and tumor growth (Chan-juan et al., 2020). Other terpenoids also contribute to renal therapeutics. Morroniside, a secoiridoid metabolite from Cornus officinalis Siebold and Zucc (Cornaceae), attenuates lipid metabolism disorder-driven chronic kidney disease by activating AMPKα/TFEB-mediated lipophagy (Zhang C. et al., 2025). Specifically, morroniside promotes AMPKα phosphorylation, triggering TFEB nuclear translocation to upregulate lipophagy, thereby enhancing ectopic lipid droplet clearance in high-fat/high-fructose diet-fed mice and palmitic acid-injured renal tubular cells (Zhang C. et al., 2025). Geniposide, an iridoid glycoside from Gardenia jasminoides J. Ellis (Rubiaceae), exerts renoprotective effects in DKD primarily by enhancing autophagy and reducing oxidative stress. It activates the AMPK/ULK1 autophagy pathway through phosphorylation of AMPK and ULK1, while simultaneously inhibiting AKT phosphorylation, reducing 4-HNE accumulation, TUNEL-positive apoptotic cells, and elevating NAD(P) H quinone oxidoreductase-1 (NQO-1), manganese superoxide dismutase (MnSOD2) and glutathione peroxidase-1 (GPX-1) expression (Theodomir et al., 2021).

Characteristically obtained from medicinal plants, alkaloids like berberine reshape lipid droplet homeostasis by modulating SIRT3-mediated lipophagy, partially alleviating cardiac lipotoxicity in diabetic cardiomyopathy. Given the pathophysiological parallels between diabetic cardiomyopathy and DKD, including lipid accumulation and lipotoxicity, berberine, an isoquinoline alkaloid from Coptis chinensis Franch (Ranunculaceae), may confer analogous lipophagic benefits in DKD (Chen et al., 2025). Furthermore, berberine inhibits the mTOR/ribosomal protein S6 kinase 1 (P70S6K)/eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1) signaling axis to activate podocyte autophagy, thereby attenuating high glucose-induced podocyte apoptosis (Li et al., 2020). In induced acute kidney injury (AKI) model, berberine conferred renoprotection by regulating the histone deacetylase 4 (HDAC4)-FoxO3a axis to induce autophagy and inhibit apoptosis (Zhi et al., 2023). Berberine also upregulates Klotho expression in cisplatin-induced AKI, activating the AMPK/mTOR/ULK1/Beclin-1 autophagy pathway to mitigate oxidative injury (SOD activity increased by 86%; MDA decreased by 54%), inflammation, and cell death (Salah et al., 2025). Additionally, neferine, a bisbenzylisoquinoline alkaloid from Nelumbo nucifera Gaertn (Nelumbonaceae), protects against cisplatin-induced AKI by activating autophagy via the AMPK/mTOR pathway, significantly reducing renal injury (Li et al., 2023). Although lipid autophagy was not explicitly examined, neferine’s AMPK-driven autophagy induction aligns with mechanisms governing lipophagy, suggesting broad applicability in lipid clearance during renal injury.

Primarily extracted from diverse natural sources such as algae, polysaccharides demonstrate notable renoprotective properties. Trehalose, a non-reducing disaccharide isolated from Selaginella lepidophylla (Hook. and Grev.) Spring (Selaginellaceae), demonstrates notable renoprotective properties. Studies indicated that it alleviates renal ischemia-reperfusion injury, potentially via autophagy enhancement coupled with oxidative stress, inflammation, and apoptosis suppression (Lingling et al., 2020; Suwen et al., 2020). Specifically, Trehalose’s renoprotective effects are primarily mediated through TFEB-driven autophagy, which indirectly mitigates renal damage by clearing oxidized organelles and suppressing oxidative stress (Lingling et al., 2020; Suwen, et al., 2020). Fucoidan, a principal constituent of the Chinese medicinal preparation Haikun Shenxi, attenuates renal cellular senescence phenotypes, including SA-β-galactosidase activity and klotho/p53/p21 expression by modulating autophagy-associated AMPK/ULK1 signaling (Qian et al., 2020). Although studies on trehalose and fucoidan have not explicitly addressed lipophagy, they demonstrated that trehalose enhances global autophagy, which in turn indirectly influences lipid metabolism.

Flavonoids, derived from fruits, vegetables, and medicinal plants, have garnered considerable scientific interest owing to their antioxidant, anti-inflammatory, and antidiabetic properties, demonstrating remarkable efficacy in countering lipid dysregulation associated with DKD (Hu et al., 2021). Diosgenin, extracted from Dioscorea zingiberensis C.H.Wright (Dioscoreaceae), has garnered attention for its beneficial effects on lipid metabolism in DKD, improving lipid metabolism by regulating the miR-148b-3p/DNA methyltransferase 1 (DNMT1)/FOXO1 axis and inhibiting lipid droplet formation in human kidney-2 (HK-2) cells (Luo et al., 2025). Calycosin, an isoflavonoid metabolite from Astragalus mongholicus Bunge (Fabaceae), mitigates lipid accumulation in DKD by restoring autophagy via phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway inhibition (Zhang et al., 2025b). Marein, derived from Coreopsis tinctoria Nutt (Asteraceae), mitigated lipid accumulation by inducing lipophagy through suppression of the PI3K/AKT/mTOR pathway (Zhang et al., 2023). In sodium oleate-induced hepatoma G2 (HepG2) cells and High fat and sugar diet (HFSD)-fed mice, Marein downregulates p-PI3K, p-AKT, and p-mTOR, leading to increased LC3-II/LC3-I ratios and enhanced co-localization of autophagosomes with lipid droplets. This promotes lysosomal degradation of lipids, reducing cellular triglycerides (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) while elevating high-density lipoprotein cholesterol (HDL-C) (Zhang et al., 2023). Notably, marein promotes renal autophagy in DKD by activating the PI3K/AKT pathway while inhibiting mTOR, evidenced by upregulated LC3-II/I, Beclin-1 and ATG5 with p62 degradation, thereby improving insulin sensitivity and attenuating nephropathy in db/db mice (Li et al., 2021). Quercetin, a flavonoid abundantly present in fruits and vegetables, has been substantiated to exert beneficial regulatory effects on autophagic processes. In the context of DKD, quercetin alleviates renal fibrosis by inhibiting excessive AMPK-dependent autophagy (Lai et al., 2020). In high-fat diet/streptozotocin-induced type 2 diabetic rats and high glucose-treated rat mesangial cells, quercetin downregulated key autophagy markers, including LC3II/I, Beclin-1, ATG5, and increased P62 accumulation in kidney tissue, concurrently reducing collagen deposition (Lai et al., 2020). Conversely, In the context of metabolic dysfunction-associated steatotic liver disease (MASLD), quercetin inhibits the mTOR/Yin-Yang1 (YY1) pathway, relieving its suppression on lipophagy and enhancing autophagic flux and lipid droplet degradation, as evidenced by increased Beclin1 expression and LC3-II conversion alongside decreased p62 levels (Katsaros et al., 2024). This divergence reflects a cell-type and disease-stage-specific effect: hepatocytes under lipid overload benefit from autophagy activation, whereas rat mesangial cells exposed to chronic hyperglycemia are adversely affected by autophagy overactivation. In addition, quercetin should be regarded neither as a universal autophagy activator nor as an inhibitor. Its net effect is dictated by tissue-specific signalling networks and dosing regimens. Thus, these contrasting outcomes underscore the necessity of conducting tissue-specific dose–response studies prior to translating quercetin or any other autophagy-modulating agent into human trials for DKD.

Cross-class comparison reveals that AMPK/mTOR modulation is the most consistently reported mechanism, being independently documented for resveratrol, celastrol, geniposide, berberine and marein in at least two different DKD models each. In contrast, TFEB-mediated lysosome biogenesis has been verified only for paeonol and morroniside, while SIRT3-dependent lipophagy is presently limited to berberine in diabetic cardiomyopathy and warrants confirmation in DKD models. Simultaneous engagement of AMPK/mTOR and SIRT1/FoxO3 axes by resveratrol suggests potential synergy, whereas PI3K/AKT inhibition is confined to celastrol, calycosin and marein. This convergence indicates that distinct natural medicines have independently evolved to target the same nutrient-sensing and autophagy checkpoints. Notably, Several of the polyphenols and flavonoids discussed above have been classified as pan-assay interfering substances (PAINS) that can produce false-positive read-outs in biochemical or cell-free screens owing to metal chelation, redox reactivity, aggrega-tion, or membrane modulation (Magalhães et al., 2021). Future work should incorporate PAINS-aware chemical filters, counter-screens for aggregation and, whenever possible, orthogonal genetic or clinical trial validation.