Qiliqiangxin: A multifaceted holistic treatment for heart failure or a pharmacological probe for the identification of cardioprotective mechanisms?

Identification of active ingredients of qiliqiangxin

Elucidation of the active compounds in QLQX is challenging, since many may be poorly absorbed and have minimal bioavailability, and others may not achieve meaningful levels in target tissues. Furthermore, the stochiometric relationships between the concentration of specific ingredients in the capsules and actions on potentially relevant biological pathways remain to be fully elucidated.

One report noted high levels of the following agents in both plasma and cardiac tissue following oral administration of QLQX: astragaloside IV, ginsenoside Rb1, periplocymarin, benzoylmesaconine, benzoylhypaconine, and alisol A.¹¹ A second report that relied on the identification of compounds with bioactivity on isolated cardiomyocytes yielded astragaloside, tanshinone IIA, ginsenoside Re, songorin, calycosin-7-O-β-D-glucopyranoside, hesperidin and alisol A.¹² Similar listings of constituents (including other ginsenosides) have been published by others.^{13, 14}

The common molecules in all reports are isoprene oligomers that have a diterpenoid (C-20) or triterpenoid (C-30) structure. Astragaloside IV is a cycloartane-type triterpene glycoside; ginsenosides are triterpene saponins (triterpenoid glycosides); alisol A is a protostane triterpenoid; periplocymarin is a triterpenoid-derived cardenolide-type steroid-like cardiac glycoside; and tanshinone IIA, benzoylmesaconine, benzoylhypaconine and songorine are diterpene alkaloids. It is generally believed that plants synthesize diterpenes and triterpenes as a mechanism of host defense, but these cytoprotective properties are evolutionarily conserved, i.e. they are mediated through convergent pathways that also ameliorate stress in cardiomyocytes. Several of the ingredients of QLQX have been used individually for the treatment of patients with heart failure.^15-17

Primary results of the QUEST trial

The Qiliqiangxin in Heart Failure: Assessment of Reduction in Mortality (QUEST) investigators presented the findings of a randomized, double-blind, placebo-controlled, parallel-group, multicentre, event-driven trial at the 2023 annual meeting of the European Society of Cardiology. The trial protocol called for the 1:1 randomization of ≈3080 patients with heart failure and a reduced ejection fraction and NT-proBNP ≥450 pg/ml to double-blind treatment with QLQX (given as 4 capsules three times daily) or matching placebo, to be added to conventional therapy for heart failure.²² The prespecified primary endpoint was cardiovascular death and hospitalization for worsening heart failure. It was anticipated that 620 events would be needed to provide 80% power to discern a 20% reduction in risk, 2-sided α = 0.04628, adjusted for two interim analyses.

The trial enrolled 3119 patients (1561 to QLQX and 1558 to placebo) with heart failure (mean ejection fraction of 32%); >60% were receiving a combination of an inhibitor of the renin–angiotensin system, a beta-blocker and a mineralocorticoid receptor antagonist, 50–60% were receiving sacubtril/valsartan, but <10% were treated with an SGLT2 inhibitor. During a median of 18.2 months of double-blind treatment (with a 5% dropout rate and <0.1% patients lost to follow-up for vital status), there were 467 primary events in the placebo group and 389 primary events in the QLQX group, yielding a hazard ratio of 0.78 (95% CI 0.68–0.90; p < 0.001).¹⁰ The hazard ratios were 0.76 (95% CI 0.64–0.90; p = 0.002) for hospitalizations for heart failure and 0.83 (95% CI 0.68–0.996; p = 0.045) for cardiovascular death. The effect on hospitalization for heart failure was dominant during the first 12–18 months of treatment. Death for any reason occurred in 262 and 221 patients in the placebo and QLQX groups, respectively (p = 0.058). The effects on systolic blood pressure, heart rate, NT-proBNP and renal function were not reported. These results have not yet been published.

Assuming that the results of the QUEST trial represent a replicable benefit of QLQX, how might the blend of 11 different herbs reduce major outcomes in patients with heart failure and a reduced ejection fraction? Despite its holistic origins, there has been intense interest in identifying the molecular and cellular mechanisms of action of Chinese herbal medicines. The QUEST investigators proposed that the benefits of QLQX were mediated by signalling through peroxisome proliferator-activated receptor-gamma (PPARγ),¹⁰ but this mechanism seems highly unlikely in light of clinical trials showing an increased risk of adverse heart failure outcomes with full PPARγ and dual PPARα/γ agonists.^23-25

Diterpenes and triterpenes in traditional Chinese medicines influence signalling through nutrient deprivation and surplus pathways

Mechanistic studies of QLQX have focused on nutrient surplus and deprivation signalling in the heart during abrupt marked injury and during sustained measured stress (e.g. heart failure). This focus is predicated on numerous reports demonstrating that diterpenes and triterpenes in traditional Chinese medicines have effects on (i) nutrient surplus signalling through the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/hypoxia inducible factor 1-alpha (HIF-1α)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway; (ii) nutrient deprivation signalling through sirtuin-1 (SIRT1) and adenosine monophosphate protein kinase (AMPK); (iii) the cellular housekeeping mechanism known as autophagy (particularly the autophagic clearance of damaged mitochondria [mitophagy]); and (iv) signalling through PPAR coactivator-1alpha (PGC-1α) and its downstream transcription factors, PPARα and PPARγ.^26-28

In general, an increase in environmental and cytosolic nutrients enhances signalling through PI3K-Akt–mTOR-HIF-1α-PGC-1α-NRF2, which prioritizes cardiomyocyte growth and replication, effects that are potentiated by neuregulin-1 (NRG-1) and its ligand, Erb-B2 receptor tyrosine kinase 2 (Erbb2).^{7, 29-31} In contrast, a depletion of environmental and cytosolic nutrients augments signalling through SIRT1-AMPK-PGC-1α, which prioritizes cardiomyocyte health and survival.^{6, 7, 29, 32} Both pathways can exert important cardioprotective effects, depending on the duration and severity of cardiac stress (Figures 1 and 2). During marked abrupt stress, cardioprotection relies on upregulation of the PI3K-Akt–mTORHIF-1α-PGC-1α-NRF2 pathway, which act to ameliorate autophagic hyperactivation and the deleterious accumulation of autophagosomes and to promote mitochondrial biogenesis and antioxidant defenses^33-36; yet, such signalling is deleterious if it is sustained for long periods.^{7, 30, 37} Conversely, upregulation of SIRT1 and AMPK may be counterproductive during abrupt marked stress,³⁸ but during sustained measured stress (as is typically the case in cardiomyopathy), prolonged SIRT1-AMPK-PGC-1α signalling exerts highly favourable effects on cardiomyocyte function and viability.^{6, 8, 29}

These striking intensity- and duration-dependent differences in the effects of cellular signals are particularly characteristic of PGC-1α and its downstream effector NRF2^39-41 and may be related to the background level of autophagy. NRF2 signalling is adaptive in marked abrupt stress when autophagy is exaggerated, but is maladaptive during prolonged measured stress when autophagy is suppressed.⁴¹ Similarly, low levels of mTOR expression seen immediately after injury promote PGC-1α-mediated mitochondrial biogenesis,^{39, 42} whereas marked sustained mTOR upregulation inhibits PGC-1α-mediated mitophagy.^{30, 31, 40, 42} Measured PGC-1α upregulation protects against sustained cardiac injury,⁴³ whereas PGC-1α overexpression results in excessive mitochondrial proliferation and cardiomyopathy.⁴⁴

PGC-1α is a convergence point for nutrient surplus and deprivation signalling, mediating differential effects on PPARα and PPARγ during short- and long-term stress

PGC-1α represents a point of convergence of these mutually antagonist pathways, being activated by mTOR during the high energy demands of acute cardiac stress and by SIRT1/AMPK during the chronic stress of cardiomyopathy (Figure 3).^{40, 45}

When activated by Akt–mTOR during acute intense stress, PGC-1α signals primarily through PPARγ to enhance the entry of glucose (which is directed towards anabolism mediated by the pentose phosphate pathway) and the accumulation of cytosolic lipids, thereby mitigating excessive autophagy.^{46, 47} PPARγ agonism ameliorates hypoxia–reperfusion by reinforcing Akt–mTOR signalling, by enhancing mitochondrial biogenesis, and by upregulating NRF2 and its downstream antioxidant actions.^{48, 49} However, during chronic measured stress, mTOR and PPARγ activation promotes the development of maladaptive hypertrophy and cardiomyopathy.^{30, 50}

In contrast when activated by SIRT1/AMPK during prolonged measured stress, PGC-1α signals primarily through PPARα to augment clearance of cytosolic lipids, fatty acid oxidation and ATP generation and to promote mitochondrial health and mitophagy.^{51, 52} PPARα silencing promotes and PPARα agonism ameliorates maladaptive hypertrophy and experimental cardiomyopathy.^53-56 However, enhanced SIRT1 and PPARα signalling is detrimental during acute pressure overload stress.³⁸

Therefore, PPARα and PPARγ reflect oppositional responses to PGC-1α signalling during abrupt and prolonged stress. Chronic cardiac stress leads to upregulation of PPARγ, but downregulation of PPARα.^55-58 PPARα and PPARγ are differentially influenced by Akt/mTOR and SIRT1/AMPK. mTOR activation causes upregulation of PPARγ, but suppression of PPARα,⁵⁹ and dual PPARα/PPARγ agonism suppresses SIRT1.⁶⁰ AMPK can inhibit cardiac hypertrophy by signalling through PPARα,⁶¹ and SIRT1 binds to PPARα to promote its activity^{38, 62} and binds to PPARγ to suppress its activity.⁶³

These counterbalancing interactions are likely mediated through a PGC-1α branch point,⁶⁴ because both PPARα and PPARγ compete with each other for binding to PGC-1α (Figure 3).^{59, 64} Both PPARα and PPARγ form heterodimers with nuclear transcription factor retinoid X receptor-alpha (RXRα), which is coactivated by PGC-1α. When activated by SIRT1 and AMPK during chronic stress, PGC-1α promotes the entry and oxidation of fatty acids and augments mitochondrial health.⁶⁵ PGC-1α-deficient mice show impaired mitochondrial function, maladaptive hypertrophy, fibrosis and accelerated heart failure,⁴³ and the PPARα agonist fenofibrate ameliorates cardiac injury (in a SIRT1- and PGC-1α-dependent manner).^{55, 56} In contrast, during acute stress, PGC-1α coactivates a heterodimer of RXRα and PPARγ under the influence of the transcription factor yin-yang 1 (YY1), a target of mTOR and a promoter of mitochondrial biogenesis and oxidative functions.^{30, 39} Short-term upregulation of mTOR, PPARγ, RXRα and YY1 (and their downstream effector, NRF2) suppresses excessive autophagosome formation and exerts cardioprotective effects in acute ischaemia or pressure overload.^{34, 66-68} However, prolonged upregulation of PGC-1α, RXRα and PPARγ leads to mitochondrial oxidative dysfunction, lipid accumulation, maladaptive hypertrophy and cardiomyopathy,^{50, 69, 70} and experimental diabetic cardiomyopathy is alleviated by PPARγ silencing.⁵⁷ mTOR and PPARγ also act to upregulate NRF2,⁴¹ and sustained NRF2 activation produces excessive reductive stress with adverse effects on cardiomyopathy.^{71, 72}

The balance of PPARα/PPARγ signalling has important implications for patients with cardiomyopathy (Figure 3). The cardiac expression of PGC-1α, PPARα and downstream effectors is downregulated, but the expression of PPARγ is upregulated, in patients with hypertensive, coronary artery disease or heart failure.^73-77 The PPARα agonist fenofibrate restores PPARα signalling and reduced heart failure events in a large-scale clinical trial.⁷⁸ Conversely, both selective PPARγ and dual PPARα/PPARγ agonists have been shown to increase the risk of heart failure events in clinical trials,^23-25 and long-term activation of NRF2 (the downstream effector of PPARγ⁷⁶) with bardoxolone increased the risk of death or hospitalization for heart failure in a large-scale trial.⁷⁹ Taken collectively, these observations suggest that the balance of PGC-1α/PPARα and PGC-1α/PPARγ signalling has important effects on the course of clinical cardiomyopathy.

Mechanistic studies of qiliqiangxin in marked abrupt cardiac injury

Qiliqiangxin has been shown to attenuate experimental doxorubicin cardiotoxicity, while enhancing PI3K-Akt–mTOR signalling and suppressing autophagic hyperactivation and autophagosome accumulation.⁸³ In cardiac or cardiomyocyte injury produced by hypoxia–reperfusion, acute ischaemia, isoproterenol or hydrogen peroxide, QLQX ameliorated adverse structural and functional changes, apoptosis and autophagosome-mediated cell death while increasing Akt and mTOR phosphorylation and muting AMPK phosphorylation; the drug's cardioprotective effects were abolished by PI3K, Akt or mTOR inhibition or by AMPK hyperactivation.^84-88 QLQX prevented hyperglycaemia-induced apoptosis in neonatal rat ventricular cardiomyocytes, an effect that was accompanied by increased expression of PGC-1α, PPAR-γ and NRF2 and was attenuated by PPAR-γ antagonism.⁸⁹ In the border zone of experimental myocardial infarction,⁹⁰ QLQX ameliorated cardiomyocyte apoptosis and induced the expression of NRF2; this protective effect was abolished when NRF2 was knocked out.

Studies by the group led by Ge et al.^91-99 highlighted a role of enhanced Akt/mTOR/HIF-1α/NRG-1/Erbb2 signalling in mediating QXQL cardioprotection during acute marked injury (Figure 4). In hypoxic cardiac microvascular endothelial cells, QLQX alleviated oxidative stress, mitochondrial dysfunction and apoptosis; these benefits were accompanied by upregulation of Akt/mTOR/HIF-1α/NRG-1 signalling and downregulation of AMPK and were abolished by HIF-1α, NRG-1 and Akt silencing and by AMPK activation.^94-96 In abrupt transverse aortic constriction, QLQX attenuated apoptosis, suppressed autophagosome formation and enhanced Erbb2 signalling, effects that were abrogated by Erbb2 inhibition.^{97, 99} Similar responses were seen in cardiac microvascular endothelial cells exposed to angiotensin II; excessive autophagosome formation and apoptosis was suppressed by QLQX, and these actions were abolished by mTOR or Erbb2 inhibition.⁹⁸ In acute myocardial infarction, the cardioprotective effects of QLQX were associated with enhanced glucose uptake, upregulation of Akt, HIF-1α and NRG-1 in the border zone, and increased expression of biomarkers of vascularization; these effects were abrogated by HIF-1α inhibition.^91-93

Ingredients of qiliqiangxin responsible for effects in marked abrupt cardiac stress

Several constituents of QLQX contribute to its effect on PI3K-Akt–mTOR-HIF-1α signalling. In injury produced by hypoxia–reperfusion or doxorubicin, astragaloside IV prevented apoptosis while enhancing glucose uptake and activating the PI3K-Akt–mTOR-HIF-1α pathway.^100-102 Similarly, tanshione IIA and ginsenosides (Rb1 and Rg1) augmented glucose uptake and upregulated P13K–Akt–mTOR and HIF-1α signalling, while inhibiting autophagosome accumulation and cell death in pressure overload and hypoxia–reperfusion injury.^103-106 Acting through mTOR, tanshione IIA promoted the transcription and stability of NRF2, and its antiapoptotic effects were dampened by NRF2 silencing.³⁴

Additionally, in human pluripotent stem cell-derived cardiomyocytes, QLQX increased Ca²⁺ spark frequency, amplitude and duration, indicative of enhanced Ca²⁺ release.¹⁰⁷ Similar effects have been reported with digitalis and other plant-derived compounds with positive inotropic actions.¹⁰⁸ Several QLQX ingredients (e.g. the cardiac glycoside periplocymarin and ginsenosides) inhibit Na⁺-K⁺-ATPase.^{109, 110} Inhibition of Na⁺-K⁺-ATPase may explain the action of QLQX to enhance PI3K-Akt–mTOR signalling,^{80, 111, 112} suppress excessive autophagosome formation,⁸⁰ and prevent injury following acute pressure overload.¹¹² Given these observations, it is perplexing that the effect of QLQX on cardiac Na⁺-K⁺-ATPase has not yet been described in the medical literature.

Descriptive reports of the effects of qiliqiangxin in chronic sustained cardiac injury

The effects of QLQX have been studied in diverse models of chronic cardiac injury, characterized by ventricular remodelling and systolic dysfunction and accompanied by oxidative stress, apoptosis, inflammation and fibrosis. In experimental myocardial infarction, aortic banding, doxorubicin injury, prolonged atrial pacing and streptozotocin-induced diabetic cardiomyopathy and in spontaneously hypertensive rats, QLQX mitigated the degree of ventricular remodelling and prevented the decline in systolic function.^{84, 117-127} These changes were associated with a reduction in apoptosis and muting of proinflammatory and profibrotic pathways^{84, 117-127} and enhanced autophagic flux.¹²⁷ QLQX prevented angiotensin II-mediated differentiation of cardiac fibroblasts,¹²⁸ abolished phenylephrine-induced hypertrophy in neonatal rat ventricular cardiomyocytes,¹²⁴ and reversed the aortic endothelial dysfunction in diabetic rats.¹²⁹ In experimental heart failure and preserved ejection fraction, QLQX mitigated myocardial hypertrophy with decreased expression of proinflammatory and profibrotic biomarkers.¹³⁰ The effects were comparable to those seen with sacubitril/valsartan, but QLQX did not produce meaningful changes in blood pressure or left ventricular filling pressure.

Qiliqiangxin-mediated upregulation of PGC-1α signalling, enhanced mitochondrial autophagy and biogenesis, and normalization of nutrient metabolism

Numerous studies have evaluated the role of PGC-1α, PPARα and PPARγ in mediating the effects of QLQX in chronic cardiomyopathy (Figure 4). In chronic isoproterenol-induced injury, QLQX prevented apoptosis, remodelling and fibrosis, while upregulating PGC-1α and PPAR-γ with no effect on PI3K-Akt–mTOR signalling.¹³¹ In post-infarction remodelling, QLQX restored cardiac structure and function and prevented apoptosis and fibrosis; these benefits were accompanied by upregulation of PPARα¹³² and PPARγ^{132, 133} and of genes critical to glucose and fatty acid metabolism.^{133, 134} In spontaneous hypertensive rats and streptozotocin-induced diabetic cardiomyopathy, QLQX attenuated ventricular dysfunction, hypertrophy, apoptosis, fibrosis and mitochondrial abnormalities; these benefits were accompanied by enhanced AMPK phosphorylation⁹³ and upregulation of PGC-1α, PPARα and PPARγ along with enzymes responsible for nutrient oxidation.^{89, 93, 127, 135} In three reports,^131-133 the effects of QLQX were abrogated by T0070907, often considered to be a PPARγ inhibitor. However, T0070907 is an inverse agonist of PPARγ,¹³⁶ and thus, it interrupts basal PPARγ activity, thus enhancing cardiac vulnerability to injury independent of blocking QLQX-related effects.^{69, 137} Full PPARγ agonism is not expected to exert cardioprotective effects.^23-25

A key mechanistic role for PGC-1α is supported by several experimental studies. In monocrotaline-induced pulmonary hypertension, QLQX ameliorated right ventricular hypertrophy and fibrosis, while enhancing PGC-1α expression and mitophagy,¹³⁸ and QLQX also upregulated mitophagy in post-infarction ventricular dysfunction.¹³⁹ Exposure of H9C2 cardiomyocytes to QLQX increased the expression of PGC-1α and promoted mitochondrial biogenesis, effects that were abolished when signalling through PGC-1α was suppressed.¹⁴⁰ QLQX mitigated phenylephrine-induced hypertrophy in neonatal rat ventricular cardiomyocytes, while increasing the expression of PGC-1α; the antihypertrophic effect of QLQX was abrogated by silencing of PGC-1α.¹⁴¹

Qiliqiangxin also promoted changes in cardiomyocyte nutrient metabolism that corresponded closely to those that follow PGC-1α upregulation. In cultured H9c2 cardiomyocytes, in post-infarction and pressure-overload remodelled ventricles and in spontaneous hypertensive rats, QLQX reduced the expression of GLUT1, while enhancing the expression of GLUT4.^{93, 134, 140, 142} Normalization of glucose transporter expression was accompanied by upregulation of PGC-1α and AMPK and restoration of long-chain fatty acid uptake and oxidation in the heart.^{91, 93, 133, 134, 140, 142} These actions are features of enhanced PGC-1α and PPARα signalling.^{115, 143}

Effect of qiliqiangxin constituents on SIRT1-AMPK-PGC-1α-PPARα signalling

Several constituents of QLQX can cause upregulation of the SIRT1/AMPK/PGC-1α pathway and autophagic flux and modulate PPARα/PPARγ signalling in chronic cardiac injury and heart failure. Traditional Chinese medicines have been a rich resource of SIRT1, PGC-1α and RXRα activators (Figure 4).^{26, 27}

Astragaloside IV has been shown to protect against isoproterenol-induced cardiac hypertrophy¹⁴⁴; lipopolysaccharide-induced cardiomyocyte dysfunction and apoptosis¹⁴⁵; streptozotocin-induced diabetic cardiomyopathy¹⁴⁶; and angiotensin II-induced mitochondrial dysfunction¹⁴⁷ – effects that were accompanied by increased PGC-1α and PPARα expression and ATP production. In murine chronic heart failure produced by abdominal aortic constriction, astrogaloside IV preserved ventricular function and enhanced fatty acid oxidation, while increasing PPARα expression.¹⁴⁸

Tanshione IIA has been used for the treatment of patients with heart failure,¹⁷ and in experimental models, tanshione IIA attenuated doxorubicin cardiotoxicity,¹⁴⁹ alleviated the development of pressure overload-induced heart failure,¹⁵⁰ and preserved cardiac function and minimized oxidative stress and apoptosis in post-infarction heart failure.¹⁵¹ The effects of tanshione IIA to prevent cardiomyopathy were accompanied by increased AMPK phosphorylation, decreased mTOR phosphorylation and enhanced autophagic flux – effects that were abolished by mTOR activation.^152-154 Tanshione IIA also ameliorated diabetic cardiomyopathy and palmitic acid-induced endoplasmic reticulum stress in neonatal rat cardiomyocytes; these effects were accompanied by upregulation of SIRT1 and were abolished by SIRT1 inhibition.¹⁵⁵ In ischaemic myocardium, neocryptotanshinone promoted mitochondrial biogenesis, fatty acid oxidation and ATP production by binding directly to RXRα to upregulate both RXRα and PPARα.¹⁵⁶

Several ginsenosides have favourable effects in experimental chronic heart failure, primarily by signalling through SIRT1, AMPK and PGC-1α. Ginsenoside Rb3 mitigated ventricular remodelling and fibrosis and exerted antiapoptotic effects in models of pressure-overload heart failure and in osmotically stressed H9C2 cardiomyocytes, and these effects were accompanied by upregulation of PGC-1α, PPARα and RXRα and restoration of enzymes critical to fatty acid oxidation.^{157, 158} Ginsenoside Rb3 binds directly to RXRα,²⁷ and its cellular benefits are abrogated by coadministration of a PPARα inhibitor.^{27, 157} Ginsenoside Rg3 enhanced PPARα signalling and reduced oxidative stress,¹⁵⁹ and it augmented mitophagy and alleviated experimental heart failure.¹⁶⁰ Similar effects were seen with ginsenoside Rg1, which reduced hypertrophy, oxidative stress and proinflammatory signalling in streptozotocin induced diabetic hearts, while upregulating AMPK and PGC-1α.¹⁶¹ In post-infarction heart failure, ginsenoside Rg1 alleviated left ventricular dilatation and fibrosis and promoted mitophagy, and the enhancement of mitophagy by ginsenoside Rg1 in hydrogen-peroxide treated cardiomyocytes was prevented by SIRT1 inhibition.¹⁶² In isoproterenol-induced heart failure, ginsenosides Rb1 and Re ameliorated cardiac injury and fibrosis, while upregulating PPARα and improving mitochondrial function and fatty acid oxidation.^{163, 164}

Little is known about the effect of astragaloside IV, tanshione IIA and ginsenosides on PPARγ in the heart. However, in non-stimulated adipocytes, ginsenosides Rb1 and Re reduced inflammatory signalling and promoted the release of adiponectin, while increasing the expression of PGC-1α and PPARγ; these effects were abrogated by PPARγ antagonism.^165-167 At the same time, ginsenoside Rg3 signaled through AMPK to function as a PPARγ antagonist in adipocytes prestimulated by rosiglitazone.¹⁶⁸ Taken together, these observations suggest that ginsenosides may function as partial PPARγ agonists, i.e. stimulating PPARγ when expression is low and inhibiting PPARγ when PPARγ is activated. Many traditional Chinese medicines act as partial PPARγ agonists,^169-171 and astragaloside IV and tanshione IIA function as PPARγ agonists or antagonists depending on the experimental setting, a profile typical of partial agonists.^172-174 Importantly, when PPARγ is upregulated (as in chronic heart failure), partial PPARγ agonists act primarily as PPARγ antagonists, thus interfering with the cardiotoxicity of full PPARγ agonism.¹⁷⁵ The possibility that QLQX acts as a partial PPARγ agonist remains to be explored.

Periplocymarin is a digitalis-like cardiac glycoside that inhibits Na⁺-K⁺-ATPase, but there is limited information about its effects in heart failure models. Nevertheless, it is noteworthy that a broad range of cardiac glycosides have been shown to stimulate autophagy via an AMPK-dependent mechanism.¹⁷⁶ The effects of periplocymarin on PPARα and PPARγ signalling have not been studied, but cardiac glycosides increase PPARδ signalling and the expression of enzymes involved in fatty acid metabolism, both in isolated cardiomyocytes and in diabetes-related cardiomyopathy.^{177, 178}