Open research questions in Cholesterol and Lipid Metabolism

What the literature leaves open

• Additionally, future studies should explore structure–activity relationships (SAR) to optimize the potency and selectivity of these molecules. A key limitation of this study is the absence of experimental validation. Conversely, the regions that are sparsely populated or located in the high energy regions (blue) imply a lesser number of stable conformations, which are hardly accessed.

  Discovery of small molecule inhibitors of liver X receptor for pediatric metabolic disorders by structure based screening, modelling, dft analysis and MD simulation · 2026 · DOI

• While cholesterol accumulation has been implicated in HSCs activation, few studies have performed genome-wide transcriptomics to chart how cholesterol metabolism is remodeled during fibrogenesis [23]. How- ever, the transcriptional changes underlying this process have remained underexplored.

  Annexin A2 Is Associated with Dietary Cholesterol-Induced Metabolic Dysregulation and the Progression of Hepatic Fibrosis · 2026 · DOI

• Nevertheless, our results generate a testable hypothesis for further investigation into D-limonene as a potential lead compound for MASLD.

  D-limonene ameliorates metabolic dysfunction-associated steatotic liver disease by inhibiting the PPARγ/SCD-1 pathway and improving lipid metabolism disorders · 2026 · DOI

• Although the enzymes responsible for cholesterol esterification, namely ACAT and LCAT, have been extensively characterized, comparatively little is known about the enzymes that hydrolyze CEs back to free cholesterol. In contrast, the CE hydrolase activity of neutral lipases, including LIPE and NCEH1, remain controversial (18-22), suggesting that additional enzymes contributing to neutral CE hydrolysis likely remain unidentified.

  The Hunt for Cholesteryl Ester Hydrolases: Identification of Lipoprotein Lipase as a Cholesterylesterase · 2026 · DOI

• While its clinical relevance remains to be established, this sterol-sensitive axis not only advances our understanding of lipid homeostasis but also offers a promising new target for therapeutic intervention in MASH, addressing a critical unmet need.

  Targeting hepatic cholesterol sensing to tackle metabolic dysfunction–associated steatohepatitis · 2026 · DOI

• Therefore, the safety conclusions from this study remain preliminary, and dedicated dose-escalation and safety studies in MASH/MASLD models are warranted before clinical translation.

  Disulfiram Alleviates Metabolic Dysfunction-Associated Steatohepatitis in Mice via Inhibiting Aurora Kinase A and Restoring Autophagy · 2026 · DOI

• Several key questions remain to be addressed in future research. Can organellar dysfunction be therapeutically reversed? Directly targeting mitophagy, lysosomal acidification, or mitochon- dria-lysosome contact sites (MLCS) represents a promising but as yet largely unexplored frontier (116, 128). Whether such strategies can effectively restore organellar function in vivo and whether this restoration translates into meaningful therapeutic benefit will require systematic investigation. How stable is trained immunity in human macrophages? A critical question is whether pro-inflammatory epigenetic memory induced by oxLDL or hyperglycemia can be erased (80, 81). If so, what strategies—such as histone demethylase activators or HDAC inhibitors—might achieve this without causing unintended effects on other cell types? What are disease-specific macrophage states in humans? Single- cell RNA sequencing and spatial transcriptomics are expected to map the heterogeneity of macrophage populations within human atherosclerotic plaques and diabetic kidneys, thereby identifying disease-relevant pathogenic subsets (6). Determining how these subsets differ in their polarization–efflux coupling status will be an important step toward precision immunometabolic therapies. Can targeting organelle contact sites improve outcomes? Modulating the physical interfaces between mitochondria and lysosomes (MLCS) is a conceptually novel approach that could potentially coordinate the functions of both organelles simulta- neously (116, 128). Whether this can be achieved pharmacologically and whether it yields therapeutic effects beyond those of targeting individual organelles remain to be determined. Translation of pre-clinical strategies. Finally, translating prom- ising pre-clinical strategies—especially miRNA inhibitors and ad- vanced nanotherapeutics—into safe and effective clinical regimens remains a significant hurdle. Delivery specificity, off-target effects, long-term safety, and the potential need for patient stratification based on inflammatory and metabolic profiles are all issues that will need to be addressed. processes, macrophage phenotypic plasticity, intracellular choles- terol handling, and organelle homeostasis appear to be closely interconnected determinants of cellular adaptation to metabolic and inflammatory stress. Progressive disruption of this coordinated network contributes to maladaptive macrophage reprogramming, impaired resolution responses, and sustained tissue injury across diverse pathological contexts. Importantly, this framework provides a conceptual basis for moving beyond the traditional binary polarization model toward a more dynamic systems-level understanding of macrophage func- tional states. However, several critical questions remain unresolved, including how organelle-specific stress signals are temporally inte- grated during macrophage state transitions, whether polarization– efflux decoupling exhibits disease-specific molecular signatures, and how these processes can be quantitatively resolved in vivo. Addressing these challenges will require the integration of emerging approaches, including single-cell multi-omics, spatial metabolomics, organelle-resolved imaging, and computational sys- tems modeling. Such efforts may enable precise characterization of macrophage immunometabolic states and facilitate identification of context-dependent therapeutic vulnerabilities. Ultimately, restoring coordinated macrophage organelle func- tion and cholesterol efflux capacity may represent a promising strategy for interrupting maladaptive inflammatory circuits and promoting tissue homeostasis across chronic inflamma- tory diseases.

  Reframing macrophage polarization through cholesterol efflux: an organelle-coupled immunometabolic model · 2026 · DOI

• However, the precise mechanisms underlying these natural products’ modulation of FXR remain unclear.

  Mangiferin alleviates metabolic-associated fatty liver disease by modulating gut microbiota and FXR signaling pathway to regulate bile acid metabolism · 2026 · DOI

• Expression of the other 12 COPI proteins were not investigated because of lack of available antibodies.

  COPI Coatomer Regulates Several Steps of HDL Metabolism · 2026 · DOI

• However, the contribution of FLRT2, especially macrophage-derived FLRT2, to atherosclerosis has not been previously explored.

  FLRT2 promotes foam cell formation and atherosclerosis by inhibiting USP22-mediated ABCA1 deubiquitination · 2026 · DOI

• Impaired macrophage efferocytosis drives chronic inflammation, yet the underlying immunometabolic mechanisms remain poorly defined.

  Macrophage MERTK restrains GRAMD1A-driven mitochondrial oxysterol trafficking to limit colitis · 2026 · DOI

• Elevated circulating cholesterol is a well-established risk factor for cardiovascular disease, however, the role of intracellular cholesterol synthesis in normal endothelial function remains unclear.

  Endothelial cytochrome P450 -derived cholesterol limits angiogenesis · 2026 · DOI

• Together, these findings indicate that lower-cholesterol formula feeding triggers an early-life adaptive response along the cholesterol-bile acid axis, suggesting that dietary cholesterol warrants attention as a component of infant formula.

  Lower-cholesterol formula feeding alters the early-life cholesterol-bile acid axis in neonatal piglets · 2026 · DOI

• Cuproptosis has been implicated in lung adenocarcinoma (LUAD), but whether it contributes to the biological functions of ATPase copper transporting alpha (ATP7A) and lipoic acid synthetase (LIAS) remains unclear.

  ATP7A and LIAS promote lung adenocarcinoma progression through regulation of cuproptosis · 2026 · DOI

• Effective pulmonary immunity requires the precise spatial organization of immune cells, yet the mechanisms guiding their intratissue positioning during inflammation remain unclear.

  Macrophage-derived oxysterols organize T helper 2 cells to suppress type 1 inflammation during pulmonary fungal infection · 2026 · DOI

• The biogenesis and transport of lipoproteins are essential for systemic homeostasis and cardiometabolic health, yet how the secretory pathway acquires specialization to support high-capacity lipoprotein export remains unclear.

  Tissue-selective COPII modulator SEC16B aggravates cardiovascular disease by promoting lipid export · 2026 · DOI

• ENG has been shown to play an important role in adhesion processes in other endothelial models but its role in LSECs upon 7-K exposure remains unclear.

  Endoglin is not a mediator in 7-ketocholesterol-induced endothelial activation in liver sinusoidal endothelial cells in vitro · 2026 · DOI

• ABCG8 is involved in sterol efflux; however, its role in cancer is not well known.

  ABCG8‑mediated sterol efflux increases cancer cell progression via the LRP6/Wnt/β‑catenin signaling pathway in radiotherapy‑resistant MDA‑MB‑231 triple‑negative breast cancer cells · 2025 · DOI

• Lipid-droplet-accumulating microglia were identified in the aging mouse and human brain; however, little is known about the formation and role of lipid droplets in microglial neuroinflammation of Alzheimer's disease (AD).

  The TRPV1-PKM2-SREBP1 axis maintains microglial lipid homeostasis in Alzheimer’s disease · 2025 · DOI

• However, the exact mechanism by which cholesterol metabolism contributes to disease pathogenesis remains unclear, and there are still unknown factors.

  Cholesterol metabolism: physiological regulation and diseases · 2024 · DOI

• However, its potential efficacy in improving atherosclerosis has not yet been investigated.

  Baoyuan decoction inhibits atherosclerosis progression through suppression peroxidized fatty acid and Src/MKK4/JNK pathway-mediated CD 36 expression · 2024 · DOI

• However, the role of SREBP-1 in the development and exacerbation of these diseases remains unclear, partly because of the impossibility of inhibiting its function because of the lack of specific inhibitors.

  Discovery of Novel Binders to Sterol Regulatory Element-Binding Protein-1 by High-Throughput Screening · 2024 · DOI

• Although this pathway is negatively regulated by metabolic intermediates, little is known of the metabolites that positively regulate its activity.

  Glutamine sensing licenses cholesterol synthesis · 2024 · DOI

• SREBP pathway inhibitors have been identified, but bioavailable compounds are lacking.

  A High-Throughput Screening Platform Identifies FDA-Approved Drugs That Inhibit SREBP Pathway Activation · 2024 · DOI

• Transcriptional and enhancer dynamics following cessation of fasting (refeeding) have not been explored.

  LXR-dependent enhancer activation regulates the temporal organization of the liver’s response to refeeding leading to lipogenic gene overshoot · 2024 · DOI

Most-cited papers in Cholesterol and Lipid Metabolism

• Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease · Nature · 2011 · 5,094 citations
• A Receptor-Mediated Pathway for Cholesterol Homeostasis · Science · 1986 · 4,394 citations
• Apolipoprotein E: Cholesterol Transport Protein with Expanding Role in Cell Biology · Science · 1988 · 3,120 citations
• APOE4/4 is linked to damaging lipid droplets in Alzheimer’s disease microglia · Nature · 2024 · 471 citations
• Lipid metabolism and lipid signals in aging and longevity · Developmental Cell · 2021 · 310 citations
• Phytosterols: From Preclinical Evidence to Potential Clinical Applications · Frontiers in Pharmacology · 2021 · 268 citations
• Ferroptotic cell death triggered by conjugated linolenic acids is mediated by ACSL1 · Nature Communications · 2021 · 261 citations
• Scavenger Receptors, Oxidized LDL, and Atherosclerosis · Annals of the New York Academy of Sciences · 2001 · 242 citations
• Exhaustion-associated cholesterol deficiency dampens the cytotoxic arm of antitumor immunity · Cancer Cell · 2023 · 216 citations
• Engineered human hepatocyte organoids enable CRISPR-based target discovery and drug screening for steatosis · Nature Biotechnology · 2023 · 215 citations

Most recent work

• Anticancer Molecular Mechanisms of Phytosterols: An Updated Review on Clinical Trials · Food Science & Nutrition · 2026
• Oxysterols at the crossroads of cholesterol metabolism and cancer · Seminars in Cancer Biology · 2026
• An oral, liver-restricted LXR inverse agonist for dyslipidemia: preclinical development and phase 1 trial · Nature Medicine · 2026
• ABCA1-mediated lipid efflux restrains oxidative stress and neuroinflammation after spinal cord injury · Journal of Neuroinflammation · 2026
• ApoE4 Drives Microglial Lipid Dysregulation in Alzheimer’s Disease via Epigenetic Reprogramming of the Asxl1/LXRα–H3K4me3 Axis · Journal of Neuroinflammation · 2026
• Cholesterol metabolism in immune cells: From mechanisms to therapeutic opportunities · Immunity · 2026
• Slc7a11‐Mediated Cystine/Glutamate Antiport Reprograms Macrophage Polarization and Ameliorates Atherosclerosis · MedComm · 2026
• S-nitrosylation of HINT1 in macrophages aggravates foam cell formation and atherosclerosis · Redox Biology · 2026
• Cholesterol nose-to-brain delivery as a possible therapeutic strategy in Huntington’s disease · Translational Neurodegeneration · 2026
• Sitosterolemia Presenting as Lipid Keratopathy and Xanthomas · PEDIATRICS · 2026

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