Piotr Szpak

Pelargonium graveolens L’Hér. is a widely distributed aromatic plant that has been utilized in traditional medicine for an extended period. It is currently experiencing a surge in popularity in modern phytotherapy. The ethnopharmacological uses of this species include treatment of respiratory tract infections, digestive disorders, and analgesia. The plant’s multifaceted biological activity is attributed to the presence of monoterpenes, such as citronellol and geraniol, as well as non-volatile polyphenolic fractions and organic acids. Research has demonstrated the efficacy of PGEO (P. graveolens essential oil) in mitigating inflammation, a phenomenon attributable to the suppression of NF-κB and MAPK signaling pathways, as well as the inhibition of inflammatory mediators such as histamine, prostaglandins (PGs), and nitric oxide (NO). Furthermore, a broad spectrum of antimicrobial activity has been demonstrated against pathogens such as MRSA and Mycobacterium tuberculosis, whilst myricetin derivatives have been shown to enable the effective eradication of bacterial biofilms. It is also noteworthy that the oil’s components can reduce ACE2 receptor expression, indicating their potential to inhibit SARS-CoV-2 infection. Active compounds, such as geraniol, have been shown to modulate metabolic processes through interaction with LXR and FXR nuclear receptors. In addition, these compounds have been observed to exhibit spasmolytic effects within the gastrointestinal tract by blocking calcium channels. The influence on the HPA axis and the GABAergic system provides a scientific rationale for the plant’s traditional use in reducing stress and anxiety. Nevertheless, variations in chemical composition, determined by geographical origin, and an insufficient number of rigorous clinical data hinder the full medical implementation of this plant. It is imperative that further standardization of extracts and their verification in clinical trials is undertaken.

Lipid peroxidation (LPO) is a process where polyunsaturated fatty acids (PUFA) in cellular membranes are oxidized. This process is mediated by reactive oxygen species (ROS) and leads to the formation of reactive products, including 4-hydroxynonenal (4-HNE), malondialdehyde (MDA), and oxidized phospholipids. At low concentrations these products act as second messengers in adaptive redox signalling and metabolic homeostasis, whereas at higher concentrations they compromise membrane integrity and promote cell death. Lipid peroxidation plays a crucial role in anticancer therapies. Here we focus on three mechanistically complementary drugs—sorafenib, cisplatin, and olaparib—because each converges, directly or indirectly, on the redox/LPO axis (system xc−/GPX4 modulation, mitochondrial ROS, and SLC7A11 regulation, respectively), modulating tumor cell responses by inducing PUFA oxidation, mitochondrial dysfunction, and membrane damage. However, tumor cells have several protective pathways against oxidative stress, such as increased expression of glutathione peroxidase 4 (GPX4), the SLC7A11 system Xc, and detoxification of reactive aldehydes. Enrichment of membranes with PUFA increases susceptibility to lipid peroxidation and ferroptosis, thereby sensitizing tumor cells to therapy, whereas enrichment with monounsaturated fatty acids (MUFA), driven by the SREBP1–SCD1 axis, limits peroxidation and confers resistance. Among regulated cell death modalities, ferroptosis is strictly dependent on lipid peroxidation, whereas apoptosis, necrosis, necroptosis, pyroptosis, and immunogenic cell death can be modulated by lipid peroxidation but do not universally require it. Collectively, these mechanisms indicate that lipid peroxidation is an important—though not exclusive—determinant of anticancer drug sensitivity and resistance, and that its dual, context-dependent role (tumor-suppressive at high flux, tumor-promoting under chronic, sub-lethal exposure) must be considered when designing LPO-based therapeutic strategies.