Lipid peroxidation is a free radical-mediated chain reaction primarily targeting polyunsaturated fatty acids (PUFAs) within biological membranes. Initiated by reactive oxygen species (ROS) such as the hydroxyl radical, it leads to the formation of lipid radicals (L·), which react with oxygen to form peroxyl radicals (LOO·). These propagate the chain by abstracting hydrogen from adjacent PUFAs, generating lipid hydroperoxides (LOOHs). The decomposition of LOOHs, often catalyzed by transition metal ions like Fe²⁺or Cu⁺, yields a plethora of reactive electrophilic species (Tschuck et al., 2024). Key terminal products include malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), which are not merely inert biomarkers but active mediators of damage through their ability to form covalent adducts with proteins and DNA, altering function and triggering secondary responses (Ya et al., 2024; Monroe et al., 2025). This self-amplifying cycle (Figure 1) can lead to exponential oxidative damage, but its site of initiation and subsequent consequences are highly context-dependent, a concept central to our framework.

A central thesis of this review is that the varied clinical manifestations of lipid peroxidation are not simply due to different end-products attacking random cellular components. Instead, pathology is initiated by a predictable hierarchy of molecular targets, determined by the unique biochemical and structural environment of each tissue. This hierarchy is governed by the intersection of local lipid substrate availability, the presence of catalytic metal ions, and compartment-specific antioxidant defenses (Zheng et al., 2024; Alves et al., 2025).

In NAFLD/Metabolic Liver Disease: The inner mitochondrial membrane phospholipid cardiolipin, enriched in PUFAs and in proximity to the ROS-producing electron transport chain (ETC.), acts as an early sentinel target. Its peroxidation precedes widespread plasma membrane damage and directly impairs ETC., complex integrity and function, leading to a vicious cycle of ROS burst and bioenergetic crisis (Aoun et al., 2012).

In Atherosclerosis: The primary initial target is extracellular: the phospholipids within low-density lipoprotein (LDL). Their oxidation generates oxidized LDL (ox-LDL), which is the key ligand for scavenger receptor-mediated uptake by macrophages, driving foam cell formation and endothelial inflammation (Koc et al., 2025).

In Neurodegenerative Diseases (e.g., Alzheimer’s): Vulnerability shifts to specific protein thiol groups, particularly in the active site of the selenoenzyme glutathione peroxidase 4 (GPX4). Its inactivation acts as a molecular switch permitting unchecked lipid peroxide accumulation, committing neurons and other cells to ferroptosis, an iron-dependent form of regulated cell death (Saraev and Pratt, 2024; Ying et al., 2025).

This hierarchical understanding moves beyond description to offer a predictive and diagnostic framework, and it fundamentally restructures our analysis. The following sections will not revisit diseases individually but will trace how these distinct initial insults—whether to mitochondrial cardiolipin, extracellular LDL, or key antioxidant enzymes—converge onto common downstream pathological themes, explaining shared pathophysiology across different organs. Detecting early, organ-specific peroxidation products (e.g., oxidized cardiolipin derivatives, specific ox-LDL epitopes) could enable earlier, more targeted interventions. It also challenges the therapeutic “one-size-fits-all” approach, suggesting that interventions must be tailored to protect or restore the relevant hierarchical target in a given disease context.

The hierarchical initiation of lipid peroxidation sets in motion downstream cascades that converge on several cross-cutting pathological themes. Adhering to our proposed framework, we now abandon a conventional organ-system-based narrative. Instead, we reorganize the pathophysiology around three core propagation themes, demonstrating how the specific initial targets identified earlier funnel into these universal pathways, ultimately yielding organ-specific disease phenotypes. Theme 1:

metabolic dysregulation and bioenergetic crisis

Lipid peroxidation directly assaults cellular energy metabolism. This theme is a primary consequence when the initial target resides in energy-generating compartments, such as mitochondria in metabolic liver disease. In hepatocytes, as seen in NAFLD, peroxidation of mitochondrial membranes disrupts the ETC., reducing ATP synthesis and increasing ROS leakage. This bioenergetic crisis impairs insulin signaling and promotes gluconeogenesis, contributing to systemic insulin resistance (Zeng and Chen, 2022). Our work with liver-specific NPC1L1-overexpressing Bama miniature pigs provides a focused and critical illustration of this theme within the proposed framework. In this model, NPC1L1-driven SREBP activation increases hepatic free fatty acids (FFA), creating a pro-oxidant milieu with mitochondrial stress. This model crystallizes and validates the hierarchical target concept: the metabolic insult (high FFA) creates a local environment where the mitochondrial inner membrane (specifically cardiolipin) becomes the primary target. Its peroxidation, evidenced by elevated MDA and depressed SOD activity, directly drives the bioenergetic dysfunction and liver injury (Fanti et al., 2025; Xu et al., 2015). Critically, this model allows comparison with other NAFLD models (e.g., high-fat diet rodents). While the initiating metabolic driver may differ, the convergence on mitochondrial cardiolipin as a key early target and the subsequent propagation through bioenergetic crisis appear to be a shared, theme-based pathway, underscoring its fundamental role. It also highlights that targeting the initial metabolic driver or protecting mitochondrial integrity may be more effective than scavenging downstream radicals. Theme 2:

inflammatory and immune dysregulation

Lipid peroxidation products are potent instigators and amplifiers of inflammation. They function as damage-associated molecular patterns (DAMPs). This theme is prominently activated when initial targets generate pro-inflammatory ligands or neo-epitopes, as seen with ox-LDL in atherosclerosis or MDA/4-HNE adducts in various tissues. For instance, ox-LDL is not just a damaged particle but a key ligand that activates pattern recognition receptors on macrophages and endothelial cells, triggering NF-κB-driven production of pro-inflammatory cytokines (Prasad and Mishra, 2022). Similarly, MDA and 4-HNE form adducts with proteins, creating oxidation-specific epitopes that can be recognized by the immune system, potentially breaking tolerance and contributing to autoimmune responses (Jomova et al., 2025). In NAFLD, MDA recruits inflammatory cells, exacerbating hepatocyte death and fibrosis progression. Thus, regardless of the initial target (LDL in vessels or cellular lipids in the liver), the propagation through inflammatory amplification represents a universal thematic pathway that links oxidative damage to chronic, sterile inflammation, a central feature of many metabolic diseases. Theme 3:

ferroptosis and cell death decisions

The fate of cells experiencing severe lipid peroxidation is often determined by the ferroptosis pathway. Ferroptosis is an iron-dependent form of regulated cell death characterized by the overwhelming, GPX4-incompetent peroxidation of phospholipids containing PUFAs, particularly arachidonoyl (AA) and adrenoyl (AdA) phosphatidylethanolamines (Capel et al., 2020). This theme represents a final common pathway for cell loss and is directly linked to the failure of specific hierarchical targets within the antioxidant defense system, most notably GPX4. The hierarchy of targets concept is crucial here: In neurons, inactivation of GPX4 (the target) unleashes ferroptosis. In cancer cells, high PUFA membrane content and metabolic alterations can predispose them to ferroptosis (Lu et al., 2025). This theme transcends individual diseases, representing a final common pathway for cell loss in neurodegenerative disorders, certain forms of hepatocyte death in steatohepatitis, and even a potential Achilles’ heel for some tumors. Therapeutic modulation of ferroptosis—by inhibiting it in degenerative diseases or inducing it in cancer—represents a prime example of mechanism-targeted intervention.

These themes are not mutually exclusive but are highly interconnected and often co-exist, driven by the initial target. For example, in atherosclerosis, ox-LDL (initiating Inflammation Theme) can also promote endothelial cell ferroptosis (Luo et al., 2024). In NAFLD, mitochondrial dysfunction and cardiolipin peroxidation (Metabolic Theme) increase ROS, promoting both inflammation and ferroptosis-sensitivity, as evidenced in our NPC1L1 model and other studies (Aoun et al., 2012; Xu et al., 2015).

The progression of lipid peroxidation is modulated by a balance between promoting factors and the antioxidant defense system. Factors such as pro-oxidant transition metals (Fe, Cu), high PUFA substrate availability, and exogenous insults (UV, toxins) promote peroxidation. The body’s defense is multi-layered, including enzymatic antioxidants like superoxide dismutase (SOD), catalase, and GPX4, and non-enzymatic scavengers like vitamin E and glutathione (Noguchi et al., 2025). Within our framework, the integrity of these defenses directly influences the “hierarchy of targets.” A deficiency in a specific defense component (e.g., selenium for GPX4) can elevate its associated molecule (e.g., GPX4 thiols) to the top of the target hierarchy in susceptible tissues, thereby determining disease susceptibility and propagation theme. A critical, often overlooked aspect is the interdependence of these defenses. For example, vitamin E (α-tocopherol) terminates radical chains in membranes, but its oxidized form is recycled by vitamin C or systems involving GPX4 and selenium. Selenium deficiency can thus render vitamin E supplementation ineffective, highlighting the need for a systems view of antioxidant therapy (Cholewski et al., 2018).

Diet profoundly influences systemic susceptibility to lipid peroxidation through multiple, interconnected mechanisms. Dietary components act across our three-tiered framework: they can alter substrate availability for initial targets (Tier 1), modulate the intensity of propagation themes (Tier 2), and serve as interventions (Tier 3). Simply recommending “antioxidants” is insufficient. Key considerations include:

PUFA Balance: The ω-6 to ω-3 PUFA ratio influences membrane composition and the profile of eicosanoid signaling molecules. Higher ω-3 intake (EPA/DHA) is generally associated with anti-inflammatory and anti-peroxidative effects, partly through the production of specialized pro-resolving mediators (SPMs) (Chen et al., 2024). However, all PUFAs are susceptible to peroxidation; thus, high PUFA intake requires adequate antioxidant support.

Antioxidant Network: Dietary antioxidants (vitamins E and C, polyphenols, selenium) function as a network. Polyphenols like curcumin or EGCG may exert effects not only through direct radical scavenging but also by activating endogenous defense pathways like the NRF2-Keap1 system (Wu et al., 2011).

Pro-oxidant Load: Processed foods can deliver pre-formed lipid oxidation products and advanced glycation end products (AGEs), which directly contribute to the oxidative burden and activate inflammatory receptors like RAGE (Manoharan et al., 2024; Harlina et al., 2024; D'Cunha et al., 2022; Wang et al., 2025).

Therefore, holistic dietary patterns (e.g., Mediterranean diet) are protective likely because they favorably modulate the entire “peroxidation landscape”: reducing pro-oxidant intake, enhancing the antioxidant network, and mitigating inflammation.

Evaluating interventions through our three-tiered framework reveals why some strategies have faltered and points to more promising directions.

Direct Antioxidants: Lessons from Failure. Broad-spectrum antioxidants (vitamin E, β-carotene) aimed at the Propagation Tier have shown limited success in chronic disease trials (Saimoto et al., 2025). Reasons include poor bioavailability, inability to reach critical subcellular sites (e.g., mitochondria), and the possibility of acting as pro-oxidants. Their role may be most relevant in prevention or in combination therapies, particularly in populations with defined deficiencies.

NRF2 Activators: Boost a suite of cytoprotective genes, offering a systems-level response (Giroud et al., 2009; Hushpulian et al., 2025; Tkaczenko et al., 2025). Caveats include potential pro-tumorigenic effects with chronic activation.

Mitochondrial Protectants: Agents that stabilize cardiolipin or improve ETC., function could prevent the initial metabolic crisis in NAFLD.

Inhibitors of Pro-Oxidant Enzymes: Targeting sources of ROS like NOX4 in specific tissues can reduce the initial insult.

Our NPC1L1 model analysis within this framework suggests that inhibiting the upstream metabolic driver (e.g., intestinal cholesterol absorption or hepatic fatty acid synthesis) is a potent strategy to prevent the cascade at its origin, by removing the condition that establishes the specific target hierarchy (hepatic mitochondrial vulnerability).

Conclusion on Therapeutic Integration: Effective therapy will likely require combination strategies that concurrently: (a) reduce the initiating insult (e.g., lower FFA, sequester catalytic iron), (b) bolster specific, compromised antioxidant defenses (e.g., GPX4 support in neurons), and (c) intercept cytotoxic secondary products. Future research must prioritize the development of biomarkers that report on specific pathways activated (e.g., specific ox-phospholipids, ferroptosis signatures) to enable truly targeted and personalized interventions.